Methods and therapeutic combinations for the treatment of demyelination

ABSTRACT

The present invention provides methods for treating demyelination and associated conditions by administering at least one sterol absorption inhibitor and compositions, therapeutic combinations and methods including: (a) at least one sterol absorption inhibitor; and (b) at least one demyelination treatment which can be useful for preventing or treating demyelination and associated conditions, such as multiple sclerosis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of co-pending U.S. patentapplication Ser. No. 10/701,244, filed Nov. 4, 2003, which isincorporated herein by reference. This application claims the benefit ofpriority from U.S. Provisional Patent Application Ser. No. 60/493,318,filed Aug. 7, 2003 and U.S. Provisional Patent Application Ser. No.60/424,165, filed Nov. 6, 2002, each of which is incorporated byreference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods and therapeutic combinationsfor treating and preventing demyelination in a subject comprising theadministration of sterol absorption inhibitor(s).

2. Description

Nerve fibers are wrapped with many layers of insulation known as themyelin sheath. Like insulation around an electrical wire, the myelinsheath permits electrical impulses to be conducted along the nerve fiberwith speed and accuracy. When normal development of the myelin isimpaired (for example in subjects having Tay-Sachs disease, Niemann-Pickdisease, Gaucher's disease and Hurler's syndrome), permanent, extensiveneurological defects can result. Also, the myelin sheath can be damagedby stroke, inflammation, immune diseases, metabolic disorders, poison ordrugs. If the sheath is able to regenerate itself, normal nerve functioncan be partially or fully restored. If demyelination is extensive, theunderlying nerve can die and cause irreversible damage. Demyelination inthe central nervous system (brain and spinal cord) occurs in severalprimary demyelinating diseases, such as multiple sclerosis, acutedisseminated encephalomyelitis, adrenoleukodystrophy,adrenomyeloneuropathy, Leber's hereditary optic atrophy andHTLV-associated myelopathy.

Multiple sclerosis (“MS”) is characterized by the loss of patches ofmyelin in the nerves of the eye, brain and/or spinal cord. It isbelieved that the body produces antibodies against its own myelin thatprovoke inflammation and damage the myelin sheath. Heredity andenvironment appear to play some role in the disease, although it isbelieved that a virus or unknown antigen somehow triggers the autoimmuneprocess. Symptoms depend upon the area affected. Demyelination in nervepathways that bring signals to muscles can produce problems withmovement (motor symptoms), such as weakness, clumsiness, difficulty inwalking or maintaining balance, tremor, double vision, problems withbladder or bowel control, stiffness, unsteadiness or unusual tiredness.Demyelination in nerve pathways that bring signals to the brain cancause sensory symptoms, such as numbness, tingling, dysesthesias, visualdisturbances, sexual dysfunction, dizziness or vertigo. Magneticresonance imaging (MRI) can reveal areas of the brain that have lostmyelin, and may even distinguish areas of recent demyelination fromareas that occurred some time ago.

Treatments for multiple sclerosis include injection withbeta-interferon, which can decrease the frequency and occurrence offlare-ups and slow the progression to disability; injection withglatiramer acetate, which can reduce the frequency of relapses; oradministration of corticosteroids, such as prednisone, to relieve acutesymptoms. Recently, statins such as simvastatin and atorvastatin (HMGCoA reductase inhibitors) have been studied for their immunomodulatoryeffects in treating MS. C. Pelfrey, “ACTRIMS-ECTRIMS 2002 (Part II)”,IDDB Meeting Report, Sep. 18-21, 2002 Baltimore, Md., USA, (October 3,2002).

There is a need in the art for improved compositions and treatments fordemyelination and associated diseases such as multiple sclerosis.

SUMMARY OF THE INVENTION

In one embodiment, there is provided a method of treating or preventingdemyelination in a subject, comprising the step of administering to asubject in need of such treatment an effective amount of at least onesterol absorption inhibitor or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment, there is provided a method of treating orpreventing multiple sclerosis in a subject, comprising the step ofadministering to a subject in need of such treatment an effective amountof at least one sterol absorption inhibitor or a pharmaceuticallyacceptable salt or solvate thereof.

A method of treating or preventing demyelination in a subject isprovided, comprising the step of administering to a subject in need ofsuch treatment an effective amount of at least one sterol absorptioninhibitor represented by Formula (II) below:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present invention provides a compositioncomprising: (a) at least one sterol absorption inhibitor or apharmaceutically acceptable salt or solvate thereof and (b) at least oneantidemyelination agent.

Therapeutic combinations also are provided comprising: (a) a firstamount of at least one sterol absorption inhibitor or a pharmaceuticallyacceptable salt or solvate thereof; and (b) a second amount of at leastone antidemyelination agent, wherein the first amount and the secondamount together comprise a therapeutically effective amount for thetreatment or prevention of demyelination in a subject.

Pharmaceutical compositions for the treatment or prevention ofdemyelination in a subject, comprising a therapeutically effectiveamount of the above compounds, compositions or therapeutic combinationsand a pharmaceutically acceptable carrier also are provided.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about.”

DETAILED DESCRIPTION

According to F. Giubilei et al., “Blood Cholesterol and MRI Activity inFirst Clinical Episode Suggestive of Multiple Sclerosis”, Acta NeurolScand 2002: 106: 109-112, 111, a significant correlation was foundbetween MS disease activity and both total and LDL (low densitylipoprotein) cholesterol levels. Lesions formed by demyelination arecharacterized by the presence of foamy macrophages containingcholesterol esters. J. Newcombe et al., “Low Density Lipoprotein Uptakeby Macrophages in Multiple Sclerosis Plaques: Implication forPathogenesis”, Neuropathol. Appl. Neurobiol. 1994: 20:152-62, 152. Thereis evidence of early involvement of LDL in the development of MSlesions. F. Giubilei at 111. A large proportion of the plasma LDL entersthe parenchyma of MS plaques as a result of blood-brain barrier damageand is oxidatively modified in the lesion. Id. Lipid peroxidation andoxidized LDL uptake by infiltrating macrophages or microglial cells inearly stages of MS plaque development may play an important role indemyelination. Id.

U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787,respectively, disclose hydroxy-substituted azetidinone compounds andsubstituted β-lactam compounds useful for inhibiting the absorption ofcholesterol, thereby lowering cholesterol levels and/or inhibiting theformation of cholesterol-containing lesions in mammalian arterial walls.U.S. Pat. Nos. 5,846,966 and 5,661,145, respectively, disclosehydroxy-substituted azetidinone compounds or substituted β-lactamcompounds in combination with HMG CoA reductase inhibitors forpreventing or treating atherosclerosis and reducing plasma cholesterollevels. Such compounds can also be useful in lowering C-reactive proteinlevels in subjects.

According to the present invention, these and other sterol absorptioninhibitors discussed in detail below can be useful in preventing ortreating demyelination and its associated conditions, such as primarydemyelinating diseases including but not limited to multiple sclerosis,acute disseminated encephalomyelitis, adrenoleukodystrophy,adrenomyeloneuropathy, Leber's hereditary optic atrophy andHTLV-associated myelopathy, and other conditions characterized bydemyelination such as Tay-Sachs disease, Niemann-Pick disease, Gaucher'sdisease and Hurler's syndrome; or stroke, inflammation, immune diseases,metabolic disorders, poison or drugs.

In one embodiment, the present invention is directed to compositions,pharmaceutical compositions, therapeutic combinations, kits and methodsof treatment using the same comprising at least one (one or more) sterolabsorption inhibitor(s). Suitable sterol absorption inhibitors includesubstituted azetidinone sterol absorption inhibitors, substitutedβ-lactam sterol absorption inhibitors or combinations thereof asdiscussed in detail below. As used herein, “sterol absorption inhibitor”means a compound capable of inhibiting the absorption of one or moresterols, including but not limited to cholesterol, phytosterols (such assitosterol, campesterol, stigmasterol and avenosterol), whenadministered in a therapeutically effective (sterol absorptioninhibiting) amount to a subject, such as a mammal or human. Other usefulcompositions, pharmaceutical compositions, therapeutic combinations,kits and methods of treatment using the same comprise at least one (oneor more) 5α-stanol absorption inhibitor(s). As used herein, “5α-stanolabsorption inhibitor” means a compound capable of inhibiting theabsorption of one or more 5α-stanols (such as cholestanol,5α-campestanol, 5α-sitostanol), when administered in a therapeuticallyeffective (5α-stanol absorption inhibiting) amount to a subject, such asa mammal or human.

In a preferred embodiment, sterol or 5α-stanol absorption inhibitorsuseful in the compositions, therapeutic combinations and methods of thepresent invention are represented by Formula (I) below:

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (I) above:

Ar¹ and Ar² are independently selected from the group consisting of aryland R⁴-substituted aryl;

Ar³ is aryl or R⁵-substituted aryl;

X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-;

R and R² are independently selected from the group consisting of —OR,—O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷;

R¹ and R³ are independently selected from the group consisting ofhydrogen, lower alkyl and aryl;

q is 0 or 1; r is 0 or 1; m, n and p are independently selected from 0,1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum ofm, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;

R⁴ is 1-5 substituents independently selected from the group consistingof lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁹, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN,—NO₂ and halogen;

R⁵ is 1-5 substituents independently selected from the group consistingof —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷,—NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷,—COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷,-(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

Preferably, R⁴ is 1-3 independently selected substituents, and R⁵ ispreferably 1-3 independently selected substituents.

In a preferred embodiment, a sterol or 5α-stanol absorption inhibitor ofFormula (I) useful in the compositions, therapeutic combinations andmethods of the present invention is represented by Formula (II)(ezetimibe) below:

or a pharmaceutically acceptable salt or solvate thereof. The compoundof Formula (II) can be in anhydrous or hydrated form.

As used herein, the term “alkyl” or “lower alkyl” means straight orbranched alkyl chains having from 1 to 6 carbon atoms and “alkoxy” meansalkoxy groups having 1 to 6 carbon atoms. Non-limiting examples of loweralkyl groups include, for example methyl, ethyl, propyl, and butylgroups. Where an alkyl chain joins two other variables and is thereforebivalent, the term alkylene is used.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms, such as phenyl, naphthyl, indenyl, tetrahydronaphthylor indanyl.

The statements wherein, for example, R, R¹, R² and R³ are said to beindependently selected from a group of substituents mean that R, R¹, R²and R³ are each independently selected, but also that where an R, R¹, R²and R³ variable occurs more than once in a molecule, each occurrence isindependently selected (e.g., if R is —OR⁶, wherein R⁶ is hydrogen, R²can be —OR⁶ wherein R⁶ is lower alkyl). Those skilled in the art willrecognize that the size and nature of the substituent(s) will affect thenumber of substituents that can be present.

Compounds of Formula I can be prepared by a variety of methods wellknown to those skilled in the art, for example such as are disclosed inU.S. Pat. Nos. 5,631,365, 5,767,115, 5,846,966, 6,207,822, PCT patentapplication Ser. No. 02/079174 and PCT Patent Application WO 93/02048,each of which is incorporated herein by reference, and in the Examplebelow.

Alternative sterol absorption inhibitors useful in the compositions,therapeutic combinations and methods of the present invention arerepresented by Formula (III) below:

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (III) above:

Ar¹ is R³-substituted aryl;

Ar² is R⁴-substituted aryl;

Ar³ is R⁵-substituted aryl;

Y and Z are independently selected from the group consisting of —CH₂—,—CH(lower alkyl)- and —C(dilower alkyl)-;

A is selected from —O—, —S—, —S(O)— or —S(O)₂—;

R¹ is selected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹and —O(CO)NR⁶R⁷; R² is selected from the group consisting of hydrogen,lower alkyl and aryl; or R¹ and R² together are ═O;

q is 1, 2 or 3;

p is 0, 1, 2, 3 or 4;

R⁵ is 1-3 substituents independently selected from the group consistingof —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷,—NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂-lower alkyl,—NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, o-halogeno, m-halogeno, o-loweralkyl, m-lower alkyl, -(lower alkylene)-COOR⁶, and —CH═CH—COOR⁶;

R³ and R⁴ are independently 1-3 substituents independently selected fromthe group consisting of R⁵, hydrogen, p-lower alkyl, aryl, —NO₂, —CF₃and p-halogeno;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R⁹ islower alkyl, aryl or aryl-substituted lower alkyl.

Methods for making compounds of Formula III are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,688,990, which is incorporated herein byreference.

In another embodiment, sterol absorption inhibitors useful in thecompositions, therapeutic combinations and methods of the presentinvention are represented by Formula (IV):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (IV) above:

A is selected from the group consisting of R²-substitutedheterocycloalkyl, R²-substituted heteroaryl, R²-substituted benzofusedheterocycloalkyl, and R²-substituted benzofused heteroaryl;

Ar¹ is aryl or R³-substituted aryl;

Ar² is aryl or R⁴-substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,forms the spiro group

and

R¹ is selected from the group consisting of:

-   -   —(CH₂)_(q)—, wherein q is 2-6, provided that when Q forms a        spiro ring, q can also be zero or 1;    -   —(CH₂)_(e)-G-(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene,        —NR⁸— or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum        of e and r is 1-6;    -   —(C₂-C₆ alkenylene)-; and    -   —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is        1-5 and g is 0-5, provided that the sum of f and g is 1-6;

R⁵ is selected from:

R⁶ and R⁷ are independently selected from the group consisting of —CH₂—,—CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)=CH—; or R⁵ together with an adjacent R⁶, or R⁵ together with anadjacent R⁷, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group;

a and b are independently 0, 1, 2 or 3, provided both are not zero;provided that when R⁶ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1;provided that when R⁷ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R⁶'s can be the same or different;and provided that when b is 2 or 3, the R⁷'s can be the same ordifferent;

and when Q is a bond, R¹ also can be selected from:

where M is —O—, —S—, —S(O)— or —S(O)₂—;

X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)- and —C(di-(C₁-C₆) alkyl);

R¹⁰ and R¹² are independently selected from the group consisting of—OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵;

R¹¹ and R¹³ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, or R¹²and R¹³ together are ═O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; providedthat at least one of s and t is 1, and the sum of m, n, p, s and t is1-6; provided that when p is 0 and t is 1, the sum of m, s and n is 1-5;and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;

v is 0 or 1;

j and k are independently 1-5, provided that the sum of j, k and v is1-5;

R² is 1-3 substituents on the ring carbon atoms selected from the groupconsisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl, R¹⁷-substituted aryl,R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁-C₆ alkylene)-, NR¹⁴R¹⁵C(O)(C₁-C₆alkylene)-, —NHC(O)R¹⁶, OH, C₁-C₆ alkoxy, —OC(O)R¹⁶, —COR¹⁴,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, NO₂, —S(O)₀₋₂R¹⁶,—SO₂NR¹⁴R¹⁵ and —(C₁-C₆ alkylene)COOR¹⁴; when R² is a substituent on aheterocycloalkyl ring, R² is as defined, or is ═O or

and, where R² is a substituent on a substitutable ring nitrogen, it ishydrogen, (C₁-C₆)alkyl, aryl, (C₁-C₆)aryloxy, (C₁-C₆)alkylcarbonyl,arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—;

R³ and R⁴ are independently selected from the group consisting of 1-3substituents independently selected from the group consisting of(C₁-C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴,—O(CO)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵, —NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹,—NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵, —COR¹⁴, SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶,—O(CH₂)₁₋₁₀—COOR¹⁴, —O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁-C₆ alkylene)-COOR¹⁴,—CH═CH—COOR¹⁴, —CF₃, —CN, —NO₂ and halogen;

R⁸ is hydrogen, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl, —C(O)R¹⁴ or —COOR¹⁴;

R⁹ and R¹⁷ are independently 1-3 groups independently selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂,—NR¹⁴R¹⁵, OH and halogeno;

R¹⁴ and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl;

R¹⁶ is (C₁-C₆)alkyl, aryl or R¹⁷-substituted aryl;

R¹⁸ is hydrogen or (C₁-C₆)alkyl; and

R¹⁹ is hydrogen, hydroxy or (C₁-C₆)alkoxy.

Methods for making compounds of Formula IV are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,656,624, which is incorporated herein byreference.

In another embodiment, sterol absorption inhibitors useful in thecompositions, therapeutic combinations and methods of the presentinvention are represented by Formula (V):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (V) above:

Ar¹ is aryl, R¹⁰-substituted aryl or heteroaryl;

Ar² is aryl or R⁴-substituted aryl;

Ar³ is aryl or R⁵-substituted aryl;

X and Y are independently selected from the group consisting of —CH₂—,—CH(lower alkyl)- and —C(dilower alkyl)-;

R is —OR⁶, —O(CO)R⁶, —O(CO)OR⁹ or —O(CO)NR⁶R⁷; R¹ is hydrogen, loweralkyl or aryl; or R and R¹ together are ═O;

q is 0 or 1;

r is 0, 1 or 2;

m and n are independently 0, 1, 2, 3, 4 or 5; provided that the sum ofm, n and q is 1, 2, 3, 4 or 5;

R⁴ is 1-5 substituents independently selected from the group consistingof lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁷(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

R⁵ is 1-5 substituents independently selected from the group consistingof —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷,—NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷,—COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷,—CF₃, —CN, —NO₂, halogen, -(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and

R¹⁰ is 1-5 substituents independently selected from the group consistingof lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen.

Methods for making compounds of Formula V are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,624,920, which is incorporated herein byreference.

In another embodiment, sterol absorption inhibitors useful in thecompositions, therapeutic combinations and methods of the presentinvention are represented by Formula (VI):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein:

R₁ is

R₂ and R₃ are independently selected from the group consisting of:—CH₂—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and —C(loweralkyl)═CH—; or R₁ together with an adjacent R₂, or R₁ together with anadjacent R₃, form a —CH═CH— or a —CH═C(lower alkyl)- group;

u and v are independently 0, 1, 2 or 3, provided both are not zero;provided that when R₂ is —CH═CH— or —C(lower alkyl)═CH—, v is 1;provided that when R₃ is —CH═CH— or —C(lower alkyl)═CH—, u is 1;provided that when v is 2 or 3, the R₂'s can be the same or different;and provided that when u is 2 or 3, the R₃'s can be the same ordifferent;

R₄ is selected from B—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4 or 5;B—(CH₂)_(q)—, wherein q is 0, 1, 2, 3, 4, 5 or 6;B—(CH₂)_(e)-Z-(CH₂)_(r)—, wherein Z is —O—, —C(O)—, phenylene, —N(R₈)—or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5,provided that the sum of e and r is 0, 1, 2, 3, 4, 5 or 6; B—(C₂-C₆alkenylene)-; B—(C₄-C₆ alkadienylene)-; B—(CH₂)_(t)-Z-(C₂-C₆alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1, 2 or3, provided that the sum of t and the number of carbon atoms in thealkenylene chain is 2, 3, 4, 5 or 6; B—(CH₂)_(f)—V—(CH₂)_(g)—, wherein Vis C₃-C₆ cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;B—(CH₂)_(t)—V—(C₂-C₆ alkenylene)- or B—(C₂-C₆ alkenylene)-V—(CH₂)_(t)—,wherein V and t are as defined above, provided that the sum of t and thenumber of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;B—(CH₂)_(a)-Z-(CH₂)_(d)—V—(CH₂)_(d)—, wherein Z and V are as definedabove and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, providedthat the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH₂)_(s)—,wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or6; or

R₁ and R₄ together form the group

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selectedfrom the group consisting of pyrrolyl, pyridinyl, pyrimidinyl,pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,oxazolyl and furanyl, and for nitrogen-containing heteroaryls, theN-oxides thereof, or

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂, —N(R₈)(R₉),N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-lower alkylenyloxy-, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈, tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, -lower alkylene-C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)-, N(R₈)(R₉)C(O)(lower alkylenyloxy)- and

for substitution on ring carbon atoms, and the substituents on thesubstituted heteroaryl ring nitrogen atoms, when present, are selectedfrom the group consisting of lower alkyl, lower alkoxy, —C(O)OR₁₀,—C(O)R₁₀, OH, N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-lower alkylenyloxy-,—S(O)₂NH₂ and 2-(trimethylsilyl)-ethoxymethyl;

R₇ is 1-3 groups independently selected from the group consisting oflower alkyl, lower alkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno;

R₈ and R₉ are independently selected from H or lower alkyl;

R₁₀ is selected from lower alkyl, phenyl, R₇-phenyl, benzyl orR₇-benzyl;

R₁₁ is selected from OH, lower alkyl, phenyl, benzyl, R₇-phenyl orR₇-benzyl;

R₁₂ is selected from H, OH, alkoxy, phenoxy, benzyloxy,

—N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl;

R₁₃ is selected from —O—, —CH₂—, —NH—, —N(lower alkyl)- or —NC(O)R₁₉;

R₁₅, R₁₆ and R₁₇ are independently selected from the group consisting ofH and the groups defined for W; or R₁₅ is hydrogen and R₁₆ and R₁₇,together with adjacent carbon atoms to which they are attached, form adioxolanyl ring;

R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and

R₂₀ and R₂₁ are independently selected from the group consisting ofphenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl,indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substitutedheteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above.

Methods for making compounds of Formula VI are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,698,548, which is incorporated herein byreference.

In another embodiment, sterol absorption inhibitors useful in thecompositions, therapeutic combinations and methods of the presentinvention are represented by Formulas (VIIA) and (VIIB):

or a pharmaceutically acceptable salt or solvate thereof,wherein:

A is —CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2;

B is

B′ is

D is —(CH₂)_(m)C(O)— or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 and q is2, 3 or 4;

E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)-alkyl, wherein the alkyl isstraight or branched, saturated or containing one or more double bonds;

R is hydrogen, C₁-C₁₅ alkyl, straight or branched, saturated orcontaining one or more double bonds, or B—(CH₂)_(r)—, wherein r is 0, 1,2, or 3;

R₁, R₂, R₃, R_(1′), R_(2′), and R_(3′), are independently selected fromthe group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy,NO₂, NH₂, OH, halogeno, lower alkylamino, dilower alkylamino,—NHC(O)OR₅, R₆O₂SNH— and —S(O)₂NH₂;

R₄ is

wherein n is 0, 1, 2 or 3;

R₅ is lower alkyl; and

R₆ is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein thesubstituents are 1-3 groups independently selected from the groupconsisting of lower alkyl, lower alkoxy, carboxy, NO₂, NH₂, OH,halogeno, lower alkylamino and dilower alkylamino; or a pharmaceuticallyacceptable salt thereof or a solvate thereof.

In another embodiment, sterol absorption inhibitors useful in thecompositions and methods of the present invention are represented byFormula (VIII):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (VIII) above,

R²⁶ is H or OG¹;

G and G are independently selected from the group consisting of

H,

and

provided that when R²⁶ is H or OH, G is not H;

R, R¹ and R^(b) are independently selected from the group consisting ofH, —OH, halogeno, —NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy or —W—R³⁰;

W is independently selected from the group consisting of —NH—C(O)—,—O—C(O)—, —O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—;

R² and R⁶ are independently selected from the group consisting of H,(C₁-C₆)alkyl, aryl and aryl(C₁-C₆)alkyl;

R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are independently selected from thegroup consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyland —C(O)aryl;

R³⁰ is selected from the group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-Substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl;

R³¹ is selected from the group consisting of H and (C₁-C₄)alkyl;

T is selected from the group consisting of phenyl, furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl,thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1-3 substituents independentlyselected from the group consisting of halogeno, (C₁-C₄)alkyl, —OH,phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy, oxo,(C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C₁-C₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

Ar¹ is aryl or R¹⁰-substituted aryl;

Ar² is aryl or R¹¹-substituted aryl;

Q is a bond or, with the 3-position ring carbon of the azetidinone,forms the spiro group

and

R¹ is selected from the group consisting of

-   -   —(CH₂)_(q)—, wherein q is 2-6, provided that when Q forms a        spiro ring, q can also be zero or 1;    -   —(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene,        —NR²²— or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the        sum of e and r is 1-6;    -   —(C₂-C₆)alkenylene-; and    -   —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is        1-5 and g is 0-5, provided that the sum of f and g is 1-6;

R¹² is

R¹³ and R¹⁴ are independently selected from the group consisting of

—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group;

a and b are independently 0, 1, 2 or 3, provided both are not zero;

provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1;

provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1;

provided that when a is 2 or 3, the R¹³'s can be the same or different;and

provided that when b is 2 or 3, the R¹⁴'s can be the same or different;

and when Q is a bond, R¹ also can be:

M is —O—, —S—, —S(O)— or —S(O)₂—;

X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl);

R¹⁰ and R¹¹ are independently selected from the group consisting of 1-3substituents independently selected from the group consisting of(C₁-C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹,—O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵,—NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹,—O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆ alkylene)-COOR¹⁹,—CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen;

R¹⁵ and R¹⁷ are independently selected from the group consisting of—OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰;

R¹⁶ and R¹⁸ are independently selected from the group consisting of H,(C₁-C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷ and R¹⁸together are ═O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4;

provided that at least one of s and t is 1, and the sum of m, n, p, sand t is 1-6;

provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; andprovided that when p is 0 and s is 1, the sum of m, t and n is 1-5;

v is 0 or 1;

j and k are independently 1-5, provided that the sum of j, k and v is1-5;

and when Q is a bond and R¹ is

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyi, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R¹⁹ and R²⁰ are independently selected from the group consisting of H,(C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl;

R²¹ is (C₁-C₆)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹;

R²³ and R²⁴ are independently 1-3 groups independently selected from thegroup consisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂,—NR¹⁹R²⁰, —OH and halogeno; and

R²⁵ is H, —OH or (C₁-C₆)alkoxy.

Methods for making compounds of Formula VIII are well known to thoseskilled in the art. Non-limiting examples of suitable methods aredisclosed in U.S. Pat. No. 5,756,470, which is incorporated herein byreference.

In another embodiment, sterol absorption inhibitors useful in thecompositions and methods of the present invention are represented byFormula (IX) below:

or a pharmaceutically acceptable salt or solvate thereof, wherein inFormula (IX):

R¹ is selected from the group consisting of H, G, G¹, G², —SO₃H and—PO₃H;

G is selected from the group consisting of: H,

wherein R, R^(a) and R^(b) are each independently selected from thegroup consisting of H, —OH, halo, —NH₂, azido,(C₁-C₆)alkoxy(C₁-C₆)alkoxy or —W—R³⁰;

W is independently selected from the group consisting of —NH—C(O)—,—O—C(O)—, —O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—;

R² and R⁶ are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, acetyl, aryl and aryl(C₁-C₆)alkyl;

R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are each independently selected fromthe group consisting of H, (C₁-C₆)alkyl, acetyl, aryl(C₁-C₆)alkyl,—C(O)(C₁-C₆)alkyl and —C(O)aryl;

R³⁰ is independently selected from the group consisting ofR³²-substituted T, R³²-substituted-T-(C₁-C₆)alkyl,R³²-substituted-(C₂-C₄)alkenyl, R³²-substituted-(C₁-C₆)alkyl,R³²-substituted-(C₃-C₇)cycloalkyl and R³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl;

R³¹ is independently selected from the group consisting of H and(C₁-C₄)alkyl;

T is independently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is independently selected from 1-3 substituents which are eachindependently selected from the group consisting of H, halo,(C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy,oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C₁-C₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;

G¹ is represented by the structure:

wherein R³³ is independently selected from the group consisting ofunsubstituted alkyl, R³⁴-substituted alkyl, (R³⁵)(R³⁶)alkyl-,

R³⁴ is one to three substituents, each R³⁴ being independently selectedfrom the group consisting of HOOC—, HO—, HS—, (CH₃)S—, H₂N—,(NH₂)(NH)C(NH)—, (NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—;

R³⁵ is independently selected from the group consisting of H and NH₂—;

R³⁶ is independently selected from the group consisting of H,unsubstituted alkyl, R³⁴-substituted alkyl, unsubstituted cycloalkyl andR³⁴-substituted cycloalkyl;

G² is represented by the structure:

wherein R³⁷ and R³⁸ are each independently selected from the groupconsisting of (C₁-C₆)alkyl and aryl;

R²⁶ is one to five substituents, each R²⁶ being independently selectedfrom the group consisting of:

-   -   a) H;    -   b) —OH;    -   c) —OCH₃;    -   d) fluorine;    -   e) chlorine;    -   f) —O-G;    -   g) —O-G¹;    -   h) —O-G²;    -   i) —SO₃H; and    -   j) —PO₃H;        provided that when R¹ is H, R²⁶ is not H, —OH, —OCH₃ or —O-G;

Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl or R¹⁰-substitutedheteroaryl;

Ar² is aryl, R¹¹-substituted aryl, heteroaryl or R¹¹-substitutedheteroaryl;

L is selected from the group consisting of:

-   -   a) a covalent bond;    -   b) —(CH₂)_(q)—, wherein q is 1-6;    -   c) —(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene,        —NR²²— or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the        sum of e and r is 1-6;    -   d) —(C₂-C₆)alkenylene-;    -   e) —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆cycloalkylene, f        is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;        and    -   f)

wherein M is —O—, —S—, —S(O)— or —S(O)₂—;

X, Y and Z are each independently selected from the group consisting of—CH₂—, —CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl)-;

R⁸ is selected from the group consisting of H and alkyl;

R¹⁰ and R¹¹ are each independently selected from the group consisting of1-3 substituents which are each independently selected from the groupconsisting of (C₁-C₆)alkyl, —OR, —O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹,—O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,

—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR^(—SO) ₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆alkylene)-COOR¹⁹, —CH═CH—COOR^(·), —CF₃, —CN, —NO₂ and halo;

R¹⁵ and R¹⁷ are each independently selected from the group consisting of—OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰;

R¹⁶ and R¹⁸are each independently selected from the group consisting ofH, (C₁-C₆)alkyl and aryl;

or R¹⁵ and R¹⁶ together are ═O, or R¹⁷and R¹⁸ together are ═O;

d is 1, 2 or 3;

h is 0, 1, 2, 3 or 4;

s is 0 or 1;

t is 0 or 1;

m, n and p are each independently selected from 0-4;

provided that at least one of s and t is 1, and the sum of m, n, p, sand t is 1-6; provided that when p is 0 and t is 1, the sum of m, n andp is 1-5; and provided that when p is 0 and s is 1, the sum of m, t andn is 1-5;

v is 0 or 1;

j and k are each independently 1-5, provided that the sum of j, k and vis 1-5;

Q is a bond, —(CH₂)_(q)—, wherein q is 1-6, or, with the 3-position ringcarbon of the azetidinone, forms the spiro group

wherein R is

R¹³ and R¹⁴ are each independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group;

a and b are each independently 0, 1, 2 or 3, provided both are not zero;provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1;provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)=CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent;

and when Q is a bond and L is

then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;

R¹⁹ and R²⁰ are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl;

R²¹ is (C₁-C₆)alkyl, aryl or R²⁴-substituted aryl;

R²² is H, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹;

R²³ and R²⁴ are each independently selected from the group consisting of1-3 substituents which are each independently selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂,—NR¹⁹R²⁰, —OHand halo; and

R²⁵ is H, —OH or (C₁-C₆)alkoxy.

Examples of compounds of Formula (IX) which are useful in the methodsand combinations of the present invention and methods for making suchcompounds are disclosed in U.S. patent application Ser. No. 10/166,942,filed Jun. 11, 2002, incorporated herein by reference.

An example of a useful compound of this invention is one represented bythe formula X:

wherein R¹ is defined as above.

A more preferred compound is one represented by formula XI:

Another useful compound is represented by Formula XII:

Other useful substituted azetidinone compounds includeN-sulfonyl-2-azetidinones such as are disclosed in U.S. Pat. No.4,983,597, ethyl 4-(2-oxoazetidin-4-yl)phenoxy-alkanoates such as aredisclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p.1134-7, and diphenyl azetidinones and derivatives disclosed in U.S.Patent Publication Nos. 2002/0039774, 2002/0128252, 2002/0128253 and2002/0137689, and WO 2002/066464, each of which is incorporated byreference herein.

The compounds of Formulae I-XII can be prepared by known methods,including the methods discussed above and, for example, WO 93/02048describes the preparation of compounds wherein —R¹-Q- is alkylene,alkenylene or alkylene interrupted by a hetero atom, phenylene orcycloalkylene; WO 94/17038 describes the preparation of compoundswherein Q is a spirocyclic group; WO 95/08532 describes the preparationof compounds wherein —R¹-Q- is a hydroxy-substituted alkylene group;PCT/US95/03196 describes compounds wherein —R¹-Q- is ahydroxy-substituted alkylene attached to the Ar¹ moiety through an —O—or S(O)₀₋₂— group; and U.S. Ser. No. 08/463,619, filed Jun. 5, 1995,describes the preparation of compounds wherein —R¹-Q- is ahydroxy-substituted alkylene group attached the azetidinone ring by a—S(O)₀₋₂— group.

Compounds of the invention have at least one asymmetrical carbon atomand therefore all isomers, including enantiomers, stereoisomers,rotamers, tautomers and racemates of the compounds of Formulae I-XII arecontemplated as being part of this invention. The invention includes dand I isomers in both pure form and in admixture, including racemicmixtures. Isomers can be prepared using conventional techniques, eitherby reacting optically pure or optically enriched starting materials orby separating isomers of a compound of the Formulae I-XII. Isomers mayalso include geometric isomers, e.g., when a double bond is present.

Those skilled in the art will appreciate that for some of the compoundsof the Formulas I-XII, one isomer will show greater pharmacologicalactivity than other isomers.

Compounds of the invention with an amino group can form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those in the art. The salt is prepared by contacting the freebase form with a sufficient amount of the desired acid to produce asalt. The free base form may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumbicarbonate. The free base form differs from its respective salt formsomewhat in certain physical properties, such as solubility in polarsolvents, but the salt is otherwise equivalent to its respective freebase forms for purposes of the invention.

Certain compounds of the invention are acidic (e.g., those compoundswhich possess a carboxyl group). These compounds form pharmaceuticallyacceptable salts with inorganic and organic bases. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also included are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

As used herein, “solvate” means a molecular or ionic complex ofmolecules or ions of solvent with those of solute (for example, one ormore compounds of Formulae I-XII, isomers of the compounds of FormulaeI-XII, or prodrugs of the compounds of Formulae I-XII). Non-limitingexamples of useful solvents include polar, protic solvents such as waterand/or alcohols (for example methanol).

Prodrugs of the compounds of Formulae I-XII are contemplated as beingpart of this invention. As used herein, “prodrug” means compounds thatare drug precursors which, following administration to a patient,release the drug in vivo via some chemical or physiological process(e.g., a prodrug on being brought to the physiological pH or throughenzyme action is converted to the desired drug form).

The daily dose of the sterol absorption inhibitor(s) administered to thesubject can range from about 0.1 to about 1000 mg per day, preferablyabout 0.25 to about 50 mg/day, and more preferably about 10 mg per day,given in a single dose or 2-4 divided doses. The exact dose, however, isdetermined by the attending clinician and is dependent on the potency ofthe compound administered, the age, weight, condition and response ofthe patient.

For administration of pharmaceutically acceptable salts of the abovecompounds, the weights indicated above refer to the weight of the acidequivalent or the base equivalent of the therapeutic compound derivedfrom the salt.

The term “therapeutically effective amount” means that amount of atherapeutic agent of the composition, such as a sterol absorptioninhibitor(s), antidemyelination agent and other pharmacological ortherapeutic agents described below, that will elicit a biological ormedical response of a tissue, system, or subject that is being sought bythe administrator (such as a researcher, doctor or veterinarian) whichincludes alleviation of the symptoms of the condition or disease beingtreated and the prevention, slowing or halting of progression of thecondition (demyelination and its symptom(s)).

Examples of suitable subjects that can be treated according to themethods of the present invention include mammals, such as humans ordogs, and other animals.

As used herein, “combination therapy” or “therapeutic combination” meansthe administration of two or more therapeutic agents, such as sterolabsorption inhibitor(s) and antidemyelination agent(s), to prevent ortreat demyelination or any of its associated conditions, such as arediscussed above. As used herein, “demyelination” means insufficient orloss of myelin on the nerves. Such administration includescoadministration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single tablet or capsule having afixed ratio of active ingredients or in multiple, separate capsules foreach therapeutic agent. Also, such administration includes use of eachtype of therapeutic agent in a sequential manner. In either case, thetreatment using the combination therapy will provide beneficial effectsin treating the demyelination condition. A potential advantage of thecombination therapy disclosed herein may be a reduction in the requiredamount of an individual therapeutic compound or the overall total amountof therapeutic compounds that are effective in treating thedemyelination condition. By using a combination of therapeutic agents,the side effects of the individual compounds can be reduced as comparedto a monotherapy, which can improve patient compliance. Also,therapeutic agents can be selected to provide a broader range ofcomplimentary effects or complimentary modes of action.

In another embodiment, the present invention provides a therapeuticcombination comprising (a) a first amount of at least one sterolabsorption inhibitor or a pharmaceutically acceptable salt thereof or asolvate thereof; and (b) a second amount of at least oneantidemyelination agent or treatment, wherein the first amount and thesecond amount together comprise a therapeutically effective amount forthe treatment or prevention of demyelination or lessening oramelioration of one or more symptoms of a condition associated withdemyelination.

In another embodiment, the present invention provides a pharmaceuticalcomposition for the treatment or prevention of diabetes and/or loweringa concentration of a sterol in plasma of a subject, comprising atherapeutically effective amount of a composition comprising (a) a firstamount of at least one sterol absorption inhibitor or a pharmaceuticallyacceptable salt thereof or a solvate thereof; (b) a second amount of atleast one antidemyelination agent and (c) a pharmaceutically acceptablecarrier.

In another embodiment, the present invention provides a method oftreating or preventing demyelination in a subject, comprising the stepof administering to a subject in need of such treatment an effectiveamount of a composition comprising (a) a first amount of at least onesterol absorption inhibitor or a pharmaceutically acceptable saltthereof or a solvate thereof; and (b) a second amount of at least oneantidemyelination agent to prevent or treat demyelination or any of itssymptoms in the subject.

Useful antidemyelination agents include beta-interferon (such as AVONEX®which is available from Biogen, Inc. and BETASERON® which is availablefrom Berlex Laboratories), which can decrease the frequency andoccurrence of flare-ups and slow the progression to disability,glatiramer acetate (such as COPAXONE® which is available from TevaNeuroscience, Inc.), which can reduce the frequency of relapses, and/oradministration of corticosteroids, such as prednisone (available fromRoxane), to relieve acute symptoms. The amount of respectiveantidemyelination agent to be administered to the subject readily can bedetermined by one skilled in the art from the Physician's Desk Reference(56^(th) Ed. 2002) at pages 1013-1016, 988-995, 3306-3310 and 3064-3066,incorporated herein by reference.

Also useful with the present invention are compositions or therapeuticcombinations that can further comprise one or more pharmacological ortherapeutic agents or drugs such as cholesterol biosynthesis inhibitorsand/or lipid-lowering agents discussed below.

Non-limiting examples of cholesterol biosynthesis inhibitors for use inthe compositions, therapeutic combinations and methods of the presentinvention include competitive inhibitors of HMG CoA reductase, therate-limiting step in cholesterol biosynthesis, squalene synthaseinhibitors, squalene epoxidase inhibitors and mixtures thereof.Non-limiting examples of suitable HMG CoA reductase inhibitors includestatins such as atorvastatin (for example LIPITOR® which is availablefrom Pfizer), lovastatin (for example MEVACOR® which is available fromMerck & Co.), pravastatin (for example PRAVACHOL® which is availablefrom Bristol Meyers Squibb), fluvastatin, simvastatin (for exampleZOCOR® which is available from Merck & Co.), cerivastatin, Cl-981,rivastatin (sodium7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate)and pitavastatin (such as NK-104 of Negma Kowa of Japan). Preferred HMGCoA reductase inhibitors include atorvastatin and simvastatin.Generally, a total daily dosage of cholesterol biosynthesis inhibitor(s)can range from about 0.1 to about 160 mg per day, and preferably about0.2 to about 80 mg/day in single or 2-3 divided doses.

Also useful with the present invention are compositions or therapeuticcombinations that can further comprise at least one (one or more)activators for peroxisome proliferator-activated receptors (PPAR), suchas peroxisome proliferator-activated receptor alpha (PPARα), peroxisomeproliferator-activated receptor gamma (PPARγ) and peroxisomeproliferator-activated receptor delta (PPARδ). PPARα activator compoundsare useful for, among other things, lowering triglycerides, moderatelylowering LDL levels and increasing HDL levels. Useful examples of PPARαactivators include fibrates, such as clofibrate, gemfibrozil andfenofibrate. The PPAR activator(s) are administered in a therapeuticallyeffective amount to treat the specified condition, for example in adaily dose preferably ranging from about 50 to about 3000 mg per day.

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more bile acid sequestrants suchas cholestyramine, colestipol and colesevelam hydrochloride. Generally,a total daily dosage of bile acid sequestrant(s) can range from about 1to about 50 grams per day, and preferably about 2 to about 16 grams perday in single or 2-4 divided doses.

The compositions or treatments of the present invention can furthercomprise one or more ileal bile acid transport (“IBAT”) inhibitors (orapical sodium co-dependent bile acid transport (“ASBT”) inhibitors)coadministered with or in combination with the peroxisomeproliferator-activated receptor activator(s) and sterol absorptioninhibitor(s) discussed above. The IBAT inhibitors can inhibit bile acidtransport to reduce LDL cholesterol levels. Non-limiting examples ofsuitable IBAT inhibitors include benzothiepines such as are disclosed inPCT Patent Application WO 00/38727 which is incorporated herein byreference. Generally, a total daily dosage of IBAT inhibitor(s) canrange from about 0.01 to about 1000 mg/day, and preferably about 0.1 toabout 50 mg/day in single or 2-4 divided doses.

The compositions or treatments of the present invention can furthercomprise nicotinic acid (niacin) and/or derivatives thereof, such asNIASPAN® (niacin extended-release tablets) which are available from Kos.Generally, a total daily dosage of nicotinic acid or a derivativethereof can range from about 500 to about 10,000 mg/day, preferablyabout 1000 to about 8000 mg/day, and more preferably about 3000 to about6000 mg/day in single or divided doses.

The compositions or treatments of the present invention can furthercomprise one or more AcylCoA:Cholesterol 0-acyltransferase (“ACAT”)Inhibitors, which can reduce LDL and VLDL levels. Non-limiting examplesof useful ACAT inhibitors include avasimibe. Generally, a total dailydosage of ACAT inhibitor(s) can range from about 0.1 to about 1000mg/day in single or 2-4 divided doses.

The compositions or treatments of the present invention can furthercomprise one or more Cholesteryl Ester Transfer Protein (“CETP”)Inhibitors. CETP is responsible for the exchange or transfer ofcholesteryl ester carrying HDL and triglycerides in VLDL. Non-limitingexamples of suitable CETP inhibitors are disclosed in PCT PatentApplication No. WO 00/38721 and U.S. Pat. No. 6,147,090, which areincorporated herein by reference. Generally, a total daily dosage ofCETP inhibitor(s) can range from about 0.01 to about 1000 mg/day, andpreferably about 0.5 to about 20 mg/kg body weight/day in single ordivided doses.

The compositions or treatments of the present invention can furthercomprise probucol or derivatives thereof, which can reduce LDL levels.Generally, a total daily dosage of probucol or derivatives thereof canrange from about 10 to about 2000 mg/day, and preferably about 500 toabout 1500 mg/day in single or 2-4 divided doses.

The compositions or treatments of the present invention can furthercomprise low-density lipoprotein (LDL) receptor activators such asHOE-402, an imidazolidinyl-pyrimidine derivative that directlystimulates LDL receptor activity. Generally, a total daily dosage of LDLreceptor activator(s) can range from about 1 to about 1000 mg/day insingle or 2-4 divided doses.

The compositions or treatments of the present invention can furthercomprise fish oil, which contains Omega 3 fatty acids (3-PUFA), whichcan reduce VLDL and triglyceride levels. Generally, a total daily dosageof fish oil or Omega 3 fatty acids can range from about 1 to about 30grams per day in single or 2-4 divided doses.

The compositions or treatments of the present invention can furthercomprise natural water soluble fibers, such as psyllium, guar, oat andpectin, which can reduce cholesterol levels. Generally, a total dailydosage of natural water soluble fibers can range from about 0.1 to about10 grams per day in single or 2-4 divided doses.

The compositions or treatments of the present invention can furthercomprise plant sterols, plant stanols and/or fatty acid esters of plantstanols, such as sitostanol ester used in BENECOL® margarine, which canreduce cholesterol levels. Generally, a total daily dosage of plantsterols, plant stanols and/or fatty acid esters of plant stanols canrange from about 0.5 to about 20 grams per day in single or 2-4 divideddoses.

The compositions or treatments of the present invention can furthercomprise antioxidants, such as probucol, tocopherol, ascorbic acid,β-carotene and selenium, or vitamins such as vitamin B₆ or vitamin B₁₂.Generally, a total daily dosage of antioxidants or vitamins can rangefrom about 0.05 to about 10 grams per day in single or 2-4 divideddoses.

The compositions or treatments of the present invention can furthercomprise monocyte and macrophage inhibitors such as polyunsaturatedfatty acids, gene therapy and use of recombinant proteins such asrecombinant apo E. Generally, a total daily dosage of these agents canrange from about 0.01 to about 1000 mg/day in single or 2-4 divideddoses.

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more cardiovascular agents orblood modifiers.

Mixtures of any of the pharmacological or therapeutic agents describedabove can be used in the compositions and therapeutic combinations ofthese other embodiments of the present invention.

The compositions and therapeutic combinations of the present inventioncan be administered to a subject in need of such treatment in atherapeutically effective amount to treat demyelination and itsassociated conditions as discussed above. The compositions andtreatments can be administered by any suitable means which producecontact of these compounds with the site of action in the body, forexample in the plasma, liver or small intestine of a subject.

The daily dosage for the various compositions and therapeuticcombinations described above can be administered to a subject in asingle dose or in multiple subdoses, as desired. Subdoses can beadministered 2 to 6 times per day, for example. Sustained releasedosages can be used. Where the antidemyelination agent and sterolabsorption inhibitor(s) are administered in separate dosages, the numberof doses of each component given per day may not necessarily be thesame, e.g., one component may have a greater duration of activity andwill therefore need to be administered less frequently.

The compositions, therapeutic combinations or medicaments of the presentinvention can further comprise one or more pharmaceutically acceptablecarriers, one or more excipients and/or one or more additives. Thepharmaceutical compositions can comprise about 1 to about 99 weightpercent of active ingredient (such as one or more compounds of FormulaI-XII), and preferably about 5 to about 95 percent active ingredient.

Useful pharmaceutically acceptable carriers can be either solid, liquidor gas. Non-limiting examples of pharmaceutically acceptable carriersinclude solids and/or liquids such as magnesium carbonate, magnesiumstearate, talc, sugar, lactose, ethanol, glycerol, water and the like.The amount of carrier in the treatment composition or therapeuticcombination can range from about 5 to about 99 weight percent of thetotal weight of the treatment composition or therapeutic combination.Non-limiting examples of suitable pharmaceutically acceptable excipientsand additives include non-toxic compatible fillers, binders such asstarch, polyvinyl pyrrolidone or cellulose ethers, disintegrants such assodium starch glycolate, crosslinked polyvinyl pyrrolidone orcroscarmellose sodium, buffers, preservatives, anti-oxidants,lubricants, flavorings, thickeners, coloring agents, wetting agents suchas sodium lauryl sulfate, emulsifiers and the like. The amount ofexcipient or additive can range from about 0.1 to about 95 weightpercent of the total weight of the treatment composition or therapeuticcombination. One skilled in the art would understand that the amount ofcarrier(s), excipients and additives (if present) can vary. Furtherexamples of pharmaceutically acceptable carriers and methods ofmanufacture for various compositions can be found in A. Gennaro (ed.),Remington: The Science and Practice of Pharmacy, 20^(th) Edition,(2000), Lippincott Williams & Wilkins, Baltimore, Md.

Useful solid form preparations include powders, tablets, dispersiblegranules, capsules, cachets and suppositories. An example of apreparation of a preferred solid form dosage formulation is providedbelow.

Useful liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also useful are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

In another embodiment, the present invention provides the use of atleast one compound represented by Formulae (I-XII) for manufacture of amedicament (such as one of the compositions discussed above) for thetreatment of demyelination and its associated conditions.

The following formulation exemplifies one of the dosage forms of thisinvention. In the formulation, the term “Active Compound I” designates asterol absorption inhibitor such as any of the compounds of FormulasI-XII described herein above and the term “Active Compound II”designates an antidemyelination agent described herein above.

EXAMPLE

Tablets No. Ingredient mq/tablet 1 Active Compound I 10 2 Lactosemonohydrate NF 55 3 Microcrystalline cellulose NF 20 4 Povidone USP(K29-32) 4 5 Croscarmellose sodium NF 8 6 Sodium lauryl sulfate NF 2 7Magnesium stearate NF 1 Total 100

In the present invention, the above-described tablet can becoadministered with an injection, tablet, capsule, etc. comprising adosage of Active Compound II as described above.

Method of Manufacture

Mix Item No. 4 with purified water in suitable mixer to form bindersolution. Spray the binder solution and then water over Items 1, 2 and 6and a portion of item 5 in a fluidized bed processor to granulate theingredients. Continue fluidization to dry the damp granules. Screen thedried granule and blend with Item No. 3 and the remainder of Item No. 5.Add Item No. 7 and mix. Compress the mixture to appropriate size andweight on a suitable tablet machine.

For coadministration in separate tablets or capsules, representativeformulations comprising a sterol absorption inhibitor such as arediscussed above are well known in the art and representativeformulations comprising an antidemyelination agent such as are discussedabove are well known in the art. It is contemplated that where the twoactive ingredients are administered as a single composition, the dosageforms disclosed above for sterol absorption inhibitors may readily bemodified using the knowledge of one skilled in the art.

Since the present invention relates to treating demyelination bytreatment with a combination of active ingredients wherein the activeingredients may be administered separately, the invention also relatesto combining separate pharmaceutical compositions in kit form. That is,a kit is contemplated wherein two separate units are combined: apharmaceutical composition comprising at least one antidemyelinationmedication and a separate pharmaceutical composition comprising at leastone sterol absorption inhibitor as described above. The kit willpreferably include directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents must be administered in different dosage forms (e.g., oraland parenteral) or are administered at different dosage intervals.

The treatment compositions and therapeutic combinations of the presentinvention can inhibit the intestinal absorption of sterols in subjectsand can be useful in the treatment and/or prevention of demyelinationand associated conditions, such as multiple sclerosis, in subjects, inparticular in mammals.

The compositions and therapeutic combinations of the present inventioncan reduce plasma concentration of at least one sterol selected from thegroup consisting of cholesterol, phytosterols (such as sitosterol,campesterol, stigmasterol and avenosterol), and/or 5α-stanols (such ascholestanol, 5α-campestanol, 5α-sitostanol), and mixtures thereof. Theplasma concentration can be reduced by administering to a subject inneed of such treatment an effective amount of at least one treatmentcomposition comprising at least one sterol or 5α-stanol absorptioninhibitor described above. The reduction in plasma concentration ofsterols or 5α-stanols can range from about 1 to about 70 percent, andpreferably about 10 to about 50 percent. Methods of measuring serumtotal blood cholesterol and total LDL cholesterol are well known tothose skilled in the art and for example include those disclosed in PCTWO 99/38498 at page 11, incorporated by reference herein. Methods ofdetermining levels of other sterols in serum are disclosed in H. Gyllinget al., “Serum Sterols During Stanol Ester Feeding in a MildlyHypercholesterolemic Population”, J. Lipid Res. 40: 593-600 (1999),incorporated by reference herein.

These sterol absorption inhibitors can be useful in treating orpreventing vascular inflammation. Vascular stimuli to mammals, such ascellular injury or inflammation, may lead to the production of variousproteins, commonly called acute response proteins, in the body. Oneparticular type of acute phase protein is C-reactive protein (CRP).Manufactured in the liver and deposited in damaged tissue, CRP is foundin high levels in inflammatory fluids and in both the intimal layer ofthe atherosclerotic artery and within the lesions of atheroscleroticplaque. These sterol absorption inhibitors can be useful for lowering orcontrolling c-reactive protein blood levels in a subject to less thanabout 3.4 mg/dL. Preferably, the C-reactive protein blood levels in asubject are reduced or controlled to less than 1.0 mg/dL by the methodsof the present invention. More preferably, the C-reactive protein bloodlevels in a subject are reduced or controlled to less than 0.4 mg/dL bythe methods of the present invention. C-reactive protein assays andmethodologies for the same are available from Behring Diagnostics Inc.,of Somerville, N.J. Moreover, methods for analyzing c-reactive proteinsare described in U.S. Pat. Nos. 5,358,852; 6,040,147; and 6,277,584,whose contents are incorporated herein by reference.

Illustrating the invention is the following example of preparation of acompound of Formula II which, however, is not to be considered aslimiting the invention to their details. Unless otherwise indicated, allparts and percentages in the following examples, as well as throughoutthe specification, are by weight.

Example Preparation of Compound of Formula (II)

Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol)in CH₂Cl₂ (200 ml), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol)and triethylamine (84.7 ml, 0.61 mol) and the reaction mixture wascooled to 0° C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) wasadded as a solution in CH₂Cl₂ (375 ml) dropwise over 1 h, and thereaction was allowed to warm to 22° C. After 17 h, water and H₂SO₄ (2N,100 ml), was added the layers were separated, and the organic layer waswashed sequentially with NaOH (10%), NaCI (sat'd) and water. The organiclayer was dried over MgSO₄ and concentrated to obtain a semicrystallineproduct.

Step 2): To a solution of TiCl₄ (18.2 ml, 0.165 mol) in CH₂Cl₂ (600 ml)at 0° C., was added titanium isopropoxide (16.5 ml, 0.055 mol). After 15min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution inCH₂Cl₂ (100 ml). After 5 min., diisopropylethylamine (DIPEA) (65.2 ml,0.37 mol) was added and the reaction mixture was stirred at 0° C. for 1h, the reaction mixture was cooled to −20° C., and4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added asa solid. The reaction mixture was stirred vigorously for 4 h at −20° C.,then acetic acid was added as a solution in CH₂Cl₂ dropwise over 15 min,the reaction mixture was allowed to warm to 0° C., and H₂SO₄ (2N) wasadded. The reaction mixture was stirred an additional 1 h, the layerswere separated, washed with water, separated and the organic layer wasdried. The crude product was crystallized from ethanol/water to obtainthe pure intermediate.

Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) intoluene (100 ml) at 50° C., was added N,O-bis(trimethylsilyl)acetamide(BSA) (7.50 ml, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol)was added and the reaction mixture stirred at 50° C. for an additional 3h. The reaction mixture was cooled to 22° C., CH₃OH (10 ml), was added.The reaction mixture was washed with HCl (1N), NaHCO₃ (1N) and NaCl(sat'd.), and the organic layer was dried over MgSO₄.

Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) inCH₃OH (3 ml), was added water (1 ml) and LiOH.H₂O (102 mg, 2.4 mmole).The reaction mixture was stirred at 22° C. for 1 h and then additionalLiOH.H₂O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCl (1N)and EtOAc was added, the layers were separated, the organic layer wasdried and concentrated in vacuo. To a solution of the resultant product(0.91 g, 2.2 mmol) in CH₂Cl₂ at 22° C., was added ClCOCOCl (0.29 ml, 3.3mmol) and the mixture stirred for 16 h. The solvent was removed invacuo.

Step 5): To an efficiently stirred suspension of 4-fluorophenylzincchloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1M inTHF, 4.4 ml, 4.4 mmol) and ZnCl₂ (0.6 g, 4.4 mmol) at 4° C., was addedtetrakis(triphenyl-phosphine)palladium (0.25 g, 0.21 mmol) followed bythe product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml).The reaction was stirred for 1 h at 0° C. and then for 0.5 h at 22° C.HCl (1N, 5 ml) was added and the mixture was extracted with EtOAc. Theorganic layer was concentrated to an oil and purified by silica gelchromatography to obtain1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone:

HRMS calc'd for C₂₄H₁₉F₂NO₃=408.1429, found 408.1411.

Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), wasadded (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole (120 mg, 0.43 mmol) and the mixture was cooled to −20° C.After 5 min, borohydride-dimethylsulfide complex (2M in THF, 0.85 ml,1.7 mmol) was added dropwise over 0.5 h. After a total of 1.5 h , CH₃OHwas added followed by HCl (1 N) and the reaction mixture was extractedwith EtOAc to obtain 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenyl methoxy)phenyl]-2-azetidinone(compound 6A-1) as an oil. ¹H in CDCl₃ d H3=4.68. J=2.3 Hz. Cl (M⁺H)500.

Use of (S)-tetra-hydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole gives the corresponding3(R)-hydroxypropyl azetidinone (compound 6B-1). ¹H in CDCl₃ d H3=4.69.J=2.3 Hz. Cl (M⁺H) 500.

To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml), wasadded 10% Pd/C (0.03 g) and the reaction mixture was stirred under apressure (60 psi) of H₂ gas for 16 h. The reaction mixture was filteredand the solvent was concentrated to obtain compound 6A. Mp 164-166° C.;Cl (M⁺H) 410. [α]_(D) ²⁵=−28.1° (c 3, CH₃OH). Elemental analysis calc'dfor C₂₄H₂₁F₂NO₃: C 70.41; H 5.17; N 3.42; found C 70.25; H 5.19; N 3.54.

Similarly treat compound 6B-1 to obtain compound 6B. Mp 129.5-132.5° C.;Cl (M⁺H) 410. Elemental analysis calc'd for C₂₄H₂₁F₂NO₃: C 70.41; H5.17; N 3.42; found C 70.30; H 5.14; N 3.52.

Step 6′ (Alternative): To a solution of the product of Step 5 (0.14 g,0.3 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and thereaction was stirred under a pressure (60 psi) of H₂ gas for 16 h. Thereaction mixture was filtered and the solvent was concentrated to afforda 1:1 mixture of compounds 6A and 6B.

Hypothetical In Vivo Evaluation

The compound of Formula II (or any cholesterol absorption inhibitordiscussed above) is administered to rodents which have been induced todevelop experimental autoimmune encephalomyelitis (“EAE”), a model ofhuman multiple sclerosis and demyelinating disease. Useful rodents caninclude C57BL/6 mice (obtained from the Jackson Laboratory or CharlesRiver Laboratories) immunized with myelin oligodendrocyte protein (MOG)35-55 peptide, SJL/J (also available from Jackson Laboratory or CharlesRiver Laboratories) mice immunized with proteolipid protein (PLP)peptides, or Lewis, BN or DA rats (obtained from Charles RiverLaboratories or Harlan Laboratories) immunized with guinea pig spinalcord homogenate or myelin basic protein (MBP). All immunizations areperformed by emulsifying the inducing peptide in either incompleteFreund's adjuvant or complete Freund's adjuvant, with or withoutpertussis toxin administration (as described in Current Protocols inImmunology, Unit 15, John Wiley & Sons, Inc. NY, or Tran et al, Eur. J.Immunol. 30:1410, 2002 or H. Butzkeuven et al, Nat. Med. 8:613, 2002).

Alternatively, the compound of Formula II (or any cholesterol absorptioninhibitor discussed above) is administered to anti-MBP T cell receptortransgenic mice (as in Grewal et al Immunity 14:291, 2001), whichnaturally develop EAE disease.

Alternatively the compound of Formula II (or any cholesterol absorptioninhibitor discussed above) is administered to rodents adoptivelytransferred with MBP-specific, PLP-specific or MOG-specific T cell lines(as described in Current Protocols in Immunology, Unit 15, John Wiley &Sons, Inc. NY).

Alternatively, the compound of Formula II (or any cholesterol absorptioninhibitor discussed above) is administered to SJL/J or C57BL/6 micewhich can be induced to develop a profound demyelinating disease byintracerebral inoculation with Theiler's murine encephalomyelitis virus(as described in Pope et al, J. Immunol. 156:4050, 1994) or byintraperitoneal injection of Simliki Forest virus (as described inSoilu-Hanninen et al, J. Virol. 68:6291,1994).

The compound is administered at a dosage of 0.1-50 mg/kg/day either inthe diet or by systemic oral, subcutaneous or intraperitonealadministration over a period of 4-10 weeks. Animals are scored daily forclinical disease score as described in Current Protocols in Immunology,Unit 15, John Wiley & Sons, Inc. NY, or Tran et al, Eur. J. Immunol.30:1410, 2002 or H. Butzkeuven et al, Nat. Med. 8:613, 2002). At aspecified period of compound administration, animals are euthanized byCO₂ asphyxiation and histological, immunohistochemical and immunologicalparameters measured as in Tran et al, Eur. J. Immunol. 30:1410, 2002 orH. Butzkeuven et al, Nat. Med. 8:613, 2002. Serum lipoprotein andcholesterol measurements will be made by standard techniques well knownto those skilled in the art.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications that are within the spirit and scopeof the invention, as defined by the appended claims.

1. A method of treating demyelination in a subject, comprising the stepof administering to a subject in need of such treatment an effectiveamount of at least one sterol absorption inhibitor or a pharmaceuticallyacceptable salt or solvate thereof, wherein the at least one sterolabsorption inhibitor is selected from the group consisting of sterolabsorption inhibitors represented by the following Formulae: (a) Formula(III):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (III) above: Ar¹ is R³-substituted aryl; Ar² isR⁴-substituted aryl; Ar³ is R⁵-substituted aryl; Y and Z areindependently selected from the group consisting of —CH₂—, —CH(loweralkyl)- and —C(dilower alkyl)-; A is selected from —O—, —S—, —S(O)— or—S(O)₂—; R¹ is selected from the group consisting of —OR⁶, —O(CO)R⁶,—O(CO)OR⁹ and —O(CO)NR⁶R⁷; R² is selected from the group consisting ofhydrogen, lower alkyl and aryl; or R¹ and R² together are ═O; q is 1, 2or 3; p is 0, 1, 2, 3 or4; R⁵ is 1-3 substituents independently selectedfrom the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁹,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸,—NR⁶SO₂-lower alkyl, —NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶ R⁷,S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷,o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(loweralkylene)-COOR⁶, and —CH═CH—COOR⁶; R³ and R⁴ are independently 1-3substituents independently selected from the group consisting of R⁵,hydrogen, p-lower alkyl, aryl, —NO₂, —CF₃ and p-halogeno; R⁶, R⁷ and R⁸are independently selected from the group consisting of hydrogen, loweralkyl, aryl and aryl-substituted lower alkyl; and R⁹ is lower alkyl,aryl or aryl-substituted lower alkyl; (b) Formula (IV):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (IV) above: A is selected from the group consistingof R²-substituted heterocycloalkyl, R²-substituted heteroaryl,R²-substituted benzofused heterocycloalkyl, and R²-substitutedbenzofused heteroaryl; Ar¹ is aryl or R³-substituted aryl; Ar² is arylor R⁴-substituted aryl; Q is a bond or, with the 3-position ring carbonof the azetidinone, forms the spiro group

and R¹ is selected from the group consisting of: —(CH₂)_(q)—, wherein qis 2-6, provided that when Q forms a spiro ring, q can also be zero or1; —(CH₂)_(e)-G-(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene, —NR⁸—or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆ alkenylene)-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R⁵ is selected from:

R⁶ and R⁷ are independently selected from the group consisting of —CH₂—,—CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R⁵ together with an adjacent R⁶, or R⁵ together with anadjacent R⁷, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and b areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R⁶ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1; provided that when R⁷is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1; provided that when a is 2 or3, the R⁶'s can be the same or different; and provided that when b is 2or 3, the R⁷'s can be the same or different; and when Q is a bond, R¹also can be selected from:

where M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independentlyselected from the group consisting of —CH₂—, —CH(C₁-C₆ alkyl)- and—C(di-(C₁-C₆) alkyl); R¹⁰ and R¹² are independently selected from thegroup consisting of —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵; R¹¹and R¹³ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, or R¹²and R¹³ together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or1; t is 0 or 1; m, n and p are independently 0-4; provided that at leastone of s and t is 1, and the sum of m, n, p, s and t is 1-6; providedthat when p is 0 and t is 1, the sum of m, s and n is 1-5; and providedthat when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1;j and k are independently 1-5, provided that the sum of j, k and v is1-5; R² is 1-3 substituents on the ring carbon atoms selected from thegroup consisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl, R¹⁷-substitutedaryl, R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁-C₆ alkylene)-, NR¹⁴R¹⁵C(O)(C₁-C₆alkylene)-, —NHC(O)R¹⁶, OH, C₁-C₆ alkoxy, —OC(O)R¹⁶, —COR¹⁴,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, NO₂, —S(O)₀₋₂R¹⁶,—SO₂NR¹⁴R¹⁵ and —(C₁-C₆ alkylene)COOR¹⁴; when R²is a substituent on aheterocycloalkyl ring, R² is as defined, or is ═O or

and, where R² is a substituent on a substitutable ring nitrogen, it ishydrogen, (C₁-C₆)alkyl, aryl, (C₁-C₆)alkoxy, aryloxy,(C₁-C₆)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—; R³ and R⁴ are independentlyselected from the group consisting of 1-3 substituents independentlyselected from the group consisting of (C₁-C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴,—O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴, —O(CO)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵,—NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹, —NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵,—COR¹⁴, —SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶, —O(CH₂)₁₋₁₀—COOR¹⁴,—O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁-C₆ alkylene)-COOR¹⁴, —CH═CH—COOR¹⁴, —CF₃,—CN, —NO₂ and halogen; R⁸ is hydrogen, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl,—C(O)R¹⁴ or —COOR¹⁴; R⁹ and R¹⁷ are independently 1-3 groupsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁴R¹⁵, OH and halogeno; R¹⁴and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R¹⁶ is(C₁-C₆)alkyl, aryl or R¹⁷-substituted aryl; R¹⁸ is hydrogen or(C₁-C₆)alkyl; and R¹⁹ is hydrogen, hydroxy or (C₁-C₆)alkoxy; (c) Formula(V):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (V) above: Ar¹ is aryl, R¹⁰-substituted aryl orheteroaryl; Ar² is aryl or R⁴-substituted aryl; Ar³ is aryl orR⁵-substituted aryl; X and Y are independently selected from the groupconsisting of —CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-; R is—OR⁶, —O(CO)R⁶, —O(CO)OR⁹ or —O(CO)NR⁶R⁷; R¹ is hydrogen, lower alkyl oraryl; or R and R¹ together are ═O; q is 0 or 1; r is 0, 1 or 2; m and nare independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n andq is 1, 2, 3, 4 or 5; R⁴ is 1-5 substituents independently selected fromthe group consisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁵ is 1-5 substituents independently selected from thegroup consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂, halogen, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and R¹⁰is 1-5 substituents independently selected from the group consisting oflower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen; (d) Formula (VI):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: R₁ is

R₂ and R₃ are independently selected from the group consisting of:—CH₂—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and —C(loweralkyl)═CH—; or R₁ together with an adjacent R₂, or R₁ together with anadjacent R₃, form a —CH═CH— or a —CH═C(lower alkyl)- group; u and v areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R₂ is —CH═CH— or —C(lower alkyl)═CH—, v is 1; provided that when R₃is —CH═CH— or —C(lower alkyl)=CH—, u is 1; provided that when v is 2 or3, the R₂'s can be the same or different; and provided that when u is 2or 3, the R₃'s can be the same or different; R₄ is selected fromB—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4 or 5; B—(CH₂)_(q)—, whereinq is 0, 1, 2, 3, 4, 5 or 6; B—(CH₂)_(e)-Z-(CH₂)_(r)—, wherein Z is —O—,—C(O)—, phenylene, —N(R₈)— or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5 and ris 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3,4, 5 or 6; B—(C₂-C₆ alkenylene)-; B—(C₄-C₆ alkadienylene)-;B—(CH₂)_(t)-Z-(C₂-C₆ alkenylene)-, wherein Z is as defined above, andwherein t is 0, 1, 2 or 3, provided that the sum of t and the number ofcarbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;B—(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is 1, 2,3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and gis 1, 2, 3, 4, 5 or 6; B—(CH₂)_(t)—V—(C₂-C₆ alkenylene)- or B—(C₂-C₆alkenylene)-V—(CH₂)_(t)—, wherein V and t are as defined above, providedthat the sum of t and the number of carbon atoms in the alkenylene chainis 2, 3, 4, 5 or 6; B—(CH₂)_(a)-Z-(CH₂)_(b)—V—(CH₂)_(d)—, wherein Z andV are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; orT-(CH₂)_(s)—, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1,2, 3, 4, 5 or 6; or R₁ and R₄ together form the group

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selectedfrom the group consisting of pyrrolyl, pyridinyl, pyrimidinyl,pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,oxazolyl and furanyl, and for nitrogen-containing heteroaryls, theN-oxides thereof, or

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂,—N(R₈)(R₉),N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-lower alkylenyloxy-, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈, tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, -lower alkylene-C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)-, N(R₈)(R₉)C(O)(lower alkylenyloxy)- and

for substitution on ring carbon atoms, and the substituents on thesubstituted heteroaryl ring nitrogen atoms, when present, are selectedfrom the group consisting of lower alkyl, lower alkoxy, —C(O)OR₁₀,—C(O)R₁₀, OH, N(R₈)(R₉)-lower alkylene-,N(R₈)(R₉)-lower alkylenyloxy-,—S(O)₂NH₂ and 2-(trimethylsilyl)-ethoxymethyl; R₇ is 1-3 groupsindependently selected from the group consisting of lower alkyl, loweralkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno; R₈ and R₉ areindependently selected from H or lower alkyl; R₁₀ is selected from loweralkyl, phenyl, R₇-phenyl, benzyl or R₇-benzyl; R₁₁ is selected from OH,lower alkyl, phenyl, benzyl, R₇-phenyl or R₇-benzyl; R₁₂ is selectedfrom H, OH, alkoxy, phenoxy, benzyloxy,

—N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl; R₁₃ is selected from —O—,—CH₂—, —NH—, —N(lower alkyl)- or —NC(O)R₁₉; R₁₅, R₁₆ and R₁₇ areindependently selected from the group consisting of H and the groupsdefined for W; or R₁₅ is hydrogen and R₁₆ and R₁₇, together withadjacent carbon atoms to which they are attached, form a dioxolanylring; R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and R₂₀ andR₂₁ are independently selected from the group consisting of phenyl,W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl,indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substitutedheteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above; (e) Formula(VIIA) or (VIIB):

or a pharmaceutically acceptable salt or solvate thereof, wherein: A is—CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2; B is

B′ is

D is —(CH₂)_(m)C(O)— or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 and q is2, 3 or 4; E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)-alkyl, wherein thealkyl is straight or branched, saturated or containing one or moredouble bonds; R is hydrogen, C₁-C₁₅ alkyl, straight or branched,saturated or containing one or more double bonds, or B—(CH₂)_(r)—,wherein r is 0, 1, 2, or 3; R₁, R₂, R₃, R_(1′), R_(2′), and R_(3′) areindependently selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino,dilower alkylamino, —NHC(O)OR₅, R₆O₂SNH— and —S(O)₂NH₂; R₄ is

wherein n is 0, 1, 2 or 3; R₅ is lower alkyl; and R₆ is OH, lower alkyl,phenyl, benzyl or substituted phenyl wherein the substituents are 1-3groups independently selected from the group consisting of lower alkyl,lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino anddilower alkylamino; or a pharmaceutically acceptable salt thereof or aprodrug thereof; (f) Formula (VIII):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (VIII) above, R²⁶ is H or OG¹; G and G¹ areindependently selected from the group consisting of H,

and

provided that when R²⁶ is H or OH, G is not H; R, R^(a) and R^(b) areindependently selected from the group consisting of H, —OH, halogeno,—NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy or —W—R³⁰; W is independentlyselected from the group consisting of —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl and aryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl and —C(O)aryl; R³⁰ is selected fromthe group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is selected from thegroup consisting of H and (C₁-C₄)alkyl; T is selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl,imidazolyl and pyridyl; R³² is independently selected from 1-3substituents independently selected from the group consisting ofhalogeno, (C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy,methylenedioxy, oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl, —N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl,—C(O)—N((C₁-C₄)alkyl)₂, —C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy andpyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹, the nitrogen towhich it is attached and R³² form a pyrrolidinyl, piperidinyl,N-methyl-piperazinyl, indolinyl or morpholinyl group, or a(C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl group; Ar¹ is aryl orR¹⁰-substituted aryl; Ar² is aryl or R¹¹-substituted aryl; Q is a bondor, with the 3-position ring carbon of the azetidinone, forms the spirogroup

and R¹ is selected from the group consisting of —(CH₂)_(q)—, wherein qis 2-6, provided that when Q forms a spiro ring, q can also be zero or1; —(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²—or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆)alkenylene-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R¹² is

R¹³ and R¹⁴ are independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R¹² together with an adjacent R¹³ , or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare independently 0, 1, 2 or 3, provided both are not zero; providedthat when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1; provided thatwhen R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1; provided that when ais 2 or 3, the R¹³'s can be the same or different; and provided thatwhen b is 2 or 3, the R¹⁴'s can be the same or different; and when Q isa bond, R¹ also can be:

M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independently selectedfrom the group consisting of —CH₂—, —CH(C₁-C₆)alkyl- and—C(di-(C₁-C₆)alkyl); R¹⁰ and R¹¹ are independently selected from thegroup consisting of 1-3 substituents independently selected from thegroup consisting of (C₁-C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹,—O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen; R¹⁵ andR¹⁷ are independently selected from the group consisting of —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰; R¹⁶ and R¹⁸ are independentlyselected from the group consisting of H, (C₁-C₆)alkyl and aryl; or R¹⁵and R¹⁶ together are ═O, or R¹⁷ and R¹⁸ together are ═O; d is 1, 2 or 3;h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 0 or 1; m, n and p areindependently 0-4; provided that at least one of s and t is 1, and thesum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1,the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1,the sum of m, t and n is 1-5; v is 0 or 1; j and k are independently1-5, provided that the sum of j, k and v is 1-5; and when Q is a bondand R¹ is

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are independently selected from the group consisting of H,(C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are independently 1-3groups independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halogeno; andR²⁵ is H, —OH or (C₁-C₆)alkoxy; and (g) Formula (IX):

or a pharmaceutically acceptable salt or solvate thereof, wherein inFormula (IX): R¹ is selected from the group consisting of H, G, G¹, G²,—SO₃H and —PO₃H;

G is selected from the group consisting of: H, wherein R, R^(a) andR^(b) are each independently selected from the group consisting of H,—OH, halo, —NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)alkoxy or —W—R³⁰; W isindependently selected from the group consisting of —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ areeach independently selected from the group consisting of H,(C₁-C₆)alkyl, acetyl, aryl and aryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a)and R^(4a) are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, acetyl, aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl and—C(O)aryl; R³⁰ is independently selected from the group consisting ofR³²-substituted T, R³²-substituted-T-(C₁-C₆)alkyl,R³²-substituted-(C₂-C₄)alkenyl, R³²-substituted-(C₁-C₆)alkyl,R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is independentlyselected from the group consisting of H and (C₁-C₄)alkyl; T isindependently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R³² isindependently selected from 1-3 substituents which are eachindependently selected from the group consisting of H, halo,(C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy,oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C₁-C₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G¹ isrepresented by the structure:

wherein R³³ is independently selected from the group consisting ofunsubstituted alkyl, R³⁴-substituted alkyl, (R³⁵)(R³⁶)alkyl-,

R³⁴ is one to three substituents, each R³⁴ being independently selectedfrom the group consisting of HOOC—, HO—, HS—, (CH₃)S—, H₂N—,(NH₂)(NH)C(NH)—, (NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—; R³⁵ isindependently selected from the group consisting of H and NH₂—; R³⁶ isindependently selected from the group consisting of H, unsubstitutedalkyl, R³⁴-substituted alkyl, unsubstituted cycloalkyl andR³⁴-substituted cycloalkyl; G² is represented by the structure:

wherein R³⁷ and R³⁸ are each independently selected from the groupconsisting of (C₁-C₆)alkyl and aryl; R²⁶ is one to five substituents,each R²⁶ being independently selected from the group consisting of: a)H; b) —OH; c) —OCH₃; d) fluorine; e) chlorine; f) —O-G; g) —O-G¹; h)—O-G²; i) —SO₃H; and j) —PO₃H; provided that when R¹ is H, R²⁶ is not H,—OH, —OCH₃ or —O-G; Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl orR¹⁰-substituted heteroaryl; Ar² is aryl, R¹¹-substituted aryl,heteroaryl or R¹¹-substituted heteroaryl; L is selected from the groupconsisting of: a) a covalent bond; b) —(CH₂)_(q)—, wherein q is 1-6; c)—(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²— or—S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; d) —(C₂-C₆)alkenylene-; e) —(CH₂)_(f)—V—(CH₂)₉—, wherein V isC₃-C₆cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; and f)

wherein M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are eachindependently selected from the group consisting of —CH₂—,—CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl)-; R⁸ is selected from the groupconsisting of H and alkyl; R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of (C₁-C₆)alkyl, —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰,—NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹,—CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹,—O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆ alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃,—CN, —NO₂ and halo; R¹⁵ and R¹⁷ are each independently selected from thegroup consisting of —OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰; R¹⁶ andR¹⁸ are each independently selected from the group consisting of H,(C₁-C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷ and R¹⁸together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is1 or 1; m, n and p are each independently selected from 0-4; providedthat at least one of s and t is 1, and the sum of m, n, p, s and t is1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;v is 0 or 1; j and k are each independently 1-5, provided that the sumof j, k and v is 1-5; Q is a bond, —(CH₂)_(q)—, wherein q is 1-6, or,with the 3-position ring carbon of the azetidinone, forms the spirogroup

wherein R¹² is

R¹³ and R¹⁴ are each independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare each independently 0, 1, 2 or 3, provided both are not zero;provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1;provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent; and when Q is a bond and L is

then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are each independentlyselected from the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halo; and R²⁵ is H, —OH or(C₁-C₆)alkoxy.
 2. The method according to claim 1, wherein the at leastone sterol absorption inhibitor is administered to a subject in anamount ranging from about 0.1 to about 1000 milligrams of sterolabsorption inhibitor per day.
 3. The method according to claim 1,further comprising the step of administering at least oneantidemyelination agent to the subject.
 4. The method according to claim3, wherein the antidemyelination agent is selected from the groupconsisting of beta interferon, glatiramer acetate and corticosteroids.5. The method according to claim 1, further comprising the step ofadministering at least one HMG CoA reductase inhibitor to the subject.6. The method according to claim 5, wherein the at least one HMG CoAreductase inhibitor is atorvastatin.
 7. The method according to claim 5,wherein the at least one HMG CoA reductase inhibitor is simvastatin. 8.The method according to claim 1, wherein the subject has multiplesclerosis.
 9. A method of treating multiple sclerosis in a subject,comprising the step of administering to a subject in need of suchtreatment an effective amount of at least one sterol absorptioninhibitor of Formula (III) through (IX) of claim 1, or apharmaceutically acceptable salt or solvate thereof.
 10. A compositioncomprising: (a) at least one sterol absorption inhibitor or apharmaceutically acceptable salt or solvate thereof and (b) at least oneantidemyelination agent, wherein the at least one sterol absorptioninhibitor is selected from the group consisting of sterol absorptioninhibitors represented by the following Formulae: (a) Formula (III):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (III) above: Ar¹ is R³-substituted aryl; Ar² isR⁴-substituted aryl; Ar³ is R⁵-substituted aryl; Y and Z areindependently selected from the group consisting of —CH₂—, —CH(loweralkyl)- and —C(dilower alkyl)-; A is selected from —O—, —S—, —S(O)— or—S(O)₂—; R¹ is selected from the group consisting of —OR⁶, —O(CO)R⁶,—O(OO)OR⁹ and —O(CO)NR⁶R⁷; R² is selected from the group consisting ofhydrogen, lower alkyl and aryl; or R¹ and R² together are ═O; q is 1, 2or 3; p is 0, 1, 2, 3 or 4; R⁵ is 1-3 substituents independentlyselected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂-lower alkyl, —NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, o-halogeno, m-halogeno, o-lower alkyl, m-loweralkyl, -(lower alkylene)-COOR⁶, and —CH═CH—COOR⁶; R³ and R⁴ areindependently 1-3 substituents independently selected from the groupconsisting of R⁵, hydrogen, p-lower alkyl, aryl, —NO₂, —CF₃ andp-halogeno; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; and R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; (b)Formula (IV):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (IV) above: A is selected from the group consistingof R²-substituted heterocycloalkyl, R²-substituted heteroaryl,R²-substituted benzofused heterocycloalkyl, and R²-substitutedbenzofused heteroaryl; Ar¹ is aryl or R³-substituted aryl; Ar² is arylor R⁴-substituted aryl; Q is a bond or, with the 3-position ring carbonof the azetidinone, forms the spiro group

and R¹ is selected from the group consisting of: —(CH₂)_(q)—, wherein qis 2-6, provided that when Q forms a spiro ring, q can also be zero or1; —(CH₂)_(e)-G-(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene, —NR⁸—or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆ alkenylene)-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R⁵ is selected from:

R⁶ and R⁷ are independently selected from the group consisting of —CH₂—,—CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R⁵ together with an adjacent R⁶, or R⁵ together with anadjacent R⁷, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and b areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R⁶ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1; provided that when R⁷is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1; provided that when a is 2 or3, the R⁶'s can be the same or different; and provided that when b is 2or 3, the R⁷'s can be the same or different; and when Q is a bond, R¹also can be selected from:

where M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independentlyselected from the group consisting of —CH₂—, —CH(C₁-C₆ alkyl)- and—C(di-(C₁-C₆) alkyl); R¹⁰ and R¹² are independently selected from thegroup consisting of —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵; R¹¹and R¹³ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, or R¹²and R¹³ together are ═O; d is 1,2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or1; t is 0 or 1; m, n and p are independently 0-4; provided that at leastone of s and t is 1, and the sum of m, n, p, s and t is 1-6; providedthat when p is 0 and t is 1, the sum of m, s and n is 1-5; and providedthat when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1;j and k are independently 1-5, provided that the sum of j, k and v is1-5; R² is 1-3 substituents on the ring carbon atoms selected from thegroup consisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl, R¹⁷-substitutedaryl, R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁-C₆ alkylene)-, NR¹⁴R¹⁵C(O)(C₁-C₆alkylene)-, —NHC(O)R¹⁶, OH, C₁-C₆ alkoxy, —OC(O)R¹⁶, —COR¹⁴,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-₆)alkyl, NO₂, —S(O)₀₋₂R¹⁶,—SO₂NR¹⁴R¹⁵ and —(C₁-C₆ alkylene)COOR¹⁴; when R² is a substituent on aheterocycloalkyl ring, R² is as defined, or is ═O or

and, where R² is a substituent on a substitutable ring nitrogen, it ishydrogen, (C₁-C₆)alkyl, aryl, (C₁-C₆)alkoxy, aryloxy,(C₁-C₆)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—; R³ and R⁴ are independentlyselected from the group consisting of 1-3 substituents independentlyselected from the group consisting of (C₁-C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴,—O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴, —O(CO)NR¹⁴R¹⁵, —NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵,—NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹, —NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵,—COR¹⁴, —SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶, —O(CH₂)₁₋₁₀—COOR¹⁴,—O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁-C₆ alkylene)-COOR¹⁴, —CH═CH—COOR¹⁴, —CF₃,—CN, —NO₂ and halogen; R⁸ is hydrogen, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl,—C(O)R¹⁴ or —COOR¹⁴; R⁹ and R¹⁷ are independently 1-3 groupsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁴R¹⁵, OH and halogeno; R¹⁴and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R¹⁶ is(C₁-C₆)alkyl, aryl or R¹⁷-substituted aryl; R¹⁸ is hydrogen or(C₁-C₆)alkyl; and R¹⁹ is hydrogen, hydroxy or (C₁-C₆)alkoxy; (c) Formula(V):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (V) above: Ar¹ is aryl, R¹⁰-substituted aryl orheteroaryl; Ar² is aryl or R⁴-substituted aryl; Ar³ is aryl orR⁵-substituted aryl; X and Y are independently selected from the groupconsisting of —CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-; R is—OR⁶, —O(CO)R⁶, —O(CO)OR⁹ or —O(CO)NR⁶R⁷; R¹ is hydrogen, lower alkyl oraryl; or R and R¹ together are ═O; q is 0 or 1; r is 0, 1 or 2; m and nare independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, n andq is 1, 2, 3, 4 or 5; R⁴ is 1-5 substituents independently selected fromthe group consisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁵ is 1-5 substituents independently selected from thegroup consisting of —OR⁵, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂, halogen, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and R¹⁰is 1-5 substituents independently selected from the group consisting oflower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁶, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen; (d) Formula (VI):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: R₁ is

R₂ and R₃ are independently selected from the group consisting of:—CH₂—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and —C(loweralkyl)═CH—; or R₁ together with an adjacent R₂, or R₁ together with anadjacent R₃, form a —CH═CH— or a —CH═C(lower alkyl)- group; u and v areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R₂ is —CH═CH— or —C(lower alkyl)═CH—, v is 1; provided that when R₃is —CH═CH— or —C(lower alkyl)═CH—, u is 1; provided that when v is 2 or3, the R₂'s can be the same or different; and provided that when u is 2or 3, the R₃'s can be the same or different; R₄ is selected fromB—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4 or 5; B—(CH₂)_(q)—, whereinq is 0, 1, 2, 3, 4, 5 or 6; B—(CH₂)_(e)-Z-(CH₂)_(r)—, wherein Z is —O—,—C(O)—, phenylene, —N(R₈)— or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5 and ris 0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3,4, 5 or 6; B—(C₂-C₆ alkenylene)-; B—(C₄-C₆ alkadienylene)-;B—(CH₂)_(t)-Z-(C₂-C₆ alkenylene)-, wherein Z is as defined above, andwherein t is 0, 1, 2 or 3, provided that the sum of t and the number ofcarbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;B—(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is 1, 2,3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and gis 1, 2, 3, 4, 5 or 6; B—(CH₂)_(t)—V—(C₂-C₆ alkenylene)- or B—(C₂-C₆alkenylene)-V—(CH₂)_(t)—, wherein V and t are as defined above, providedthat the sum of t and the number of carbon atoms in the alkenylene chainis 2, 3, 4, 5 or 6; B—(CH₂)_(a)-Z-(CH₂)_(b)—V—(CH₂)_(d)—, wherein Z andV are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; orT-(CH₂)_(s)—, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1,2, 3, 4, 5 or 6; or R₁ and R₄ together form the group

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selectedfrom the group consisting of pyrrolyl, pyridinyl, pyrimidinyl,pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,oxazolyl and furanyl, and for nitrogen-containing heteroaryls, theN-oxides thereof, or

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂,—N(R₈)(R₉),N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-lower alkylenyloxy-, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈, tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, -lower alkylene-C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)-, N(R₈)(R₉)C(O)(lower alkylenyloxy)- and

for substitution on ring carbon atoms, and the substituents on thesubstituted heteroaryl ring nitrogen atoms, when present, are selectedfrom the group consisting of lower alkyl, lower alkoxy, —C(O)OR₁₀,—C(O)R₁₀, OH, N(R₈)(R₉)-lower alkylene-,N(R₈)(R₉)-lower alkylenyloxy-,—S(O)₂NH₂ and 2-(trimethylsilyl)-ethoxymethyl; R₇ is 1-3 groupsindependently selected from the group consisting of lower alkyl, loweralkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno; R₈ and R₉ areindependently selected from H or lower alkyl; R₁₀ is selected from loweralkyl, phenyl, R₇-phenyl, benzyl or R₇-benzyl; R₁₁ is selected from OH,lower alkyl, phenyl, benzyl, R₇-phenyl or R₇-benzyl; R₁₂ is selectedfrom H, OH, alkoxy, phenoxy, benzyloxy,

—N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl; R₁₃ is selected from —O—,—CH₂—, —NH—, —N(lower alkyl)- or —NC(O)R₁₉; R₁₅, R₁₆ and R₁₇ areindependently selected from the group consisting of H and the groupsdefined for W; or R₁₅ is hydrogen and R₁₆ and R₁₇, together withadjacent carbon atoms to which they are attached, form a dioxolanylring; R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and R₂₀ andR₂₁ are independently selected from the group consisting of phenyl,W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl,indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substitutedheteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above; (e) Formula(VIIA) or (VIIB):

or a pharmaceutically acceptable salt or solvate thereof, wherein: A is—CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2; B is

B′ is

D is —(CH₂)_(m)C(O)— or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 and q is2, 3 or 4; E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)-alkyl, wherein thealkyl is straight or branched, saturated or containing one or moredouble bonds; R is hydrogen, C₁-C₁₅ alkyl, straight or branched,saturated or containing one or more double bonds, or B—(CH₂)_(r)—,wherein r is 0, 1, 2, or 3; R₁, R₂, R₃, R_(1′), R_(2′), and R_(3′)areindependently selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino,dilower alkylamino, —NHC(O)OR₅, R₆O₂SNH— and —S(O)₂NH₂; R₄ is

wherein n is 0, 1, 2 or 3; R₅ is lower alkyl; and R₆ is OH, lower alkyl,phenyl, benzyl or substituted phenyl wherein the substituents are 1-3groups independently selected from the group consisting of lower alkyl,lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino anddilower alkylamino; or a pharmaceutically acceptable salt thereof or aprodrug thereof; (f) Formula (VIII):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (VIII) above, R²⁶ is H or OG¹; G and G¹ areindependently selected from the group consisting of H,

provided that when R²⁶ is H or OH, G is not H; R, R^(a) and R^(b) areindependently selected from the group consisting of H, —OH, halogeno,—NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy or —W—R³⁰; W is independentlyselected from the group consisting of —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl and aryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl and —C(O)aryl; R³⁰ is selected fromthe group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is selected from thegroup consisting of H and (C₁-C₄)alkyl; T is selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl,imidazolyl and pyridyl; R³² is independently selected from 1-3substituents independently selected from the group consisting ofhalogeno, (C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy,methylenedioxy, oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl, —N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl,—C(O)—N((C₁-C₄)alkyl)₂, —C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy andpyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹, the nitrogen towhich it is attached and R³² form a pyrrolidinyl, piperidinyl,N-methyl-piperazinyl, indolinyl or morpholinyl group, or a(C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl group; Ar¹ is aryl orR¹⁰-substituted aryl; Ar² is aryl or R¹¹-substituted aryl; Q is a bondor, with the 3-position ring carbon of the azetidinone, forms the spirogroup

and R¹ is selected from the group consisting of —(CH₂)_(q)—, wherein qis 2-6, provided that when Q forms a spiro ring, q can also be zero or1; —(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²—or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆)alkenylene-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R¹² is

R¹³ and R¹⁴ are independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)=CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare independently 0, 1, 2 or 3, provided both are not zero; providedthat when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1; provided thatwhen R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1; provided that when ais 2 or 3, the R¹³'s can be the same or different; and provided thatwhen b is 2 or 3, the R¹⁴'s can be the same or different; and when Q isa bond, R¹ also can be:

M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independently selectedfrom the group consisting of —CH₂—, —CH(C₁-C₆)alkyl- and—C(di-(C₁-C₆)alkyl); R¹⁰ and R¹¹ are independently selected from thegroup consisting of 1-3 substituents independently selected from thegroup consisting of (C_(l -C) ₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹,—O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹, —O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen; R¹⁵ andR¹⁷ are independently selected from the group consisting of —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰; R¹⁶ and R¹⁸ are independentlyselected from the group consisting of H, (C₁-C₆)alkyl and aryl; or R¹⁵and R¹⁶ together are ═O, or R¹⁷ and R¹⁸ together are ═O; d is 1, 2 or 3;h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 0 or 1; m, n and p areindependently 0-4; provided that at least one of s and t is 1, and thesum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1,the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1,the sum of m, t and n is 1-5; v is 0 or 1; j and k are independently1-5, provided that the sum of j, k and v is 1-5; and when Q is a bondand R¹ is

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are independently selected from the group consisting of H,(C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are independently 1-3groups independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halogeno; andR²⁵ is H, —OH or (C₁-C₆)alkoxy; and (g) Formula (IX):

or a pharmaceutically acceptable salt or solvate thereof, wherein inFormula (IX): R¹ is selected from the group consisting of H, G, G¹, G²,—SO₃H and —PO₃H; G is selected from the group consisting of: H,

wherein R, R^(a) and R^(b) are each independently selected from thegroup consisting of H, —OH, halo, —NH₂, azido,(C₁-C₆)alkoxy(C₁-C₆)alkoxy or —W—R³⁰; W is independently selected fromthe group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R³¹)—,—NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ are each independentlyselected from the group consisting of H, (C₁-C₆)alkyl, acetyl, aryl andaryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) are eachindependently selected from the group consisting of H, (C₁-C₆)alkyl,acetyl, aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl and —C(O)aryl; R³⁰ isindependently selected from the group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is independentlyselected from the group consisting of H and (C₁-C₄)alkyl; T isindependently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R³² isindependently selected from 1-3 substituents which are eachindependently selected from the group consisting of H, halo,(C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy,oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C₁-C₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G¹ isrepresented by the structure:

wherein R³³ is independently selected from the group consisting ofunsubstituted alkyl, R³⁴-substituted alkyl, (R³⁵)(R³⁶)alkyl-,

R³⁴ is one to three substituents, each R³⁴ being independently selectedfrom the group consisting of HOOC—, HO—, HS—, (CH₃)S—, H₂N—,(NH₂)(NH)C(NH)—, (NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—; R³⁵ isindependently selected from the group consisting of H and NH₂—; R³⁶ isindependently selected from the group consisting of H, unsubstitutedalkyl, R³⁴-substituted alkyl, unsubstituted cycloalkyl andR³⁴-substituted cycloalkyl; G² is represented by the structure:

wherein R³⁷ and R³⁸ are each independently selected from the groupconsisting of (C₁-C₆)alkyl and aryl; R²⁶ is one to five substituents,each R²⁶ being independently selected from the group consisting of: a)H; b) —OH; c) —OCH₃; d) fluorine; e) chlorine; f) —O-G; g) —O-G¹; h)—O-G²; i) —SO₃H; and j) —PO₃H; provided that when R¹ is H, R²⁶ is not H,—OH, —OCH₃ or —O-G; Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl orR¹⁰-substituted heteroaryl; Ar² is aryl, R¹¹-substituted aryl,heteroaryl or R¹¹-substituted heteroaryl; L is selected from the groupconsisting of: a) a covalent bond; b) —(CH₂)_(q)—, wherein q is 1-6; c)—(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²— or—S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; d) —(C₂-C₆)alkenylene-; e) —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; and f)

wherein M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are eachindependently selected from the group consisting of —CH₂—,—CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl)-; R⁸ is selected from the groupconsisting of H and alkyl; R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of (C₁-C₆)alkyl, —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰,—NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹,—CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹,—O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆ alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃,—CN, —NO₂ and halo; R¹⁵ and R¹⁷ are each independently selected from thegroup consisting of —OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰; R¹⁶ andR¹⁸are each independently selected from the group consisting of H,(C₁-C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷and R¹⁸together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is1 or 1; m, n and p are each independently selected from 0-4; providedthat at least one of s and t is 1, and the sum of m, n, p, s and t is1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;v is 0 or 1; j and k are each independently 1-5, provided that the sumof j, k and v is 1-5; Q is a bond, —(CH₂)_(q)—, wherein q is 1-6, or,with the 3-position ring carbon of the azetidinone, forms the spirogroup

wherein R¹² is

R¹³ and R¹⁴ are each independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)=CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare each independently 0, 1, 2 or 3, provided both are not zero;provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1;provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent; and when Q is a bond and L is

then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are each independentlyselected from the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halo; and R²⁵ is H, —OH or(C₁-C₆)alkoxy.
 11. A therapeutic combination comprising: (a) a firstamount of at least one sterol absorption inhibitor or a pharmaceuticallyacceptable salt or solvate thereof; and (b) a second amount of at leastone antidemyelination agent, wherein the first amount and the secondamount together comprise a therapeutically effective amount for thetreatment of demyelination in a subject and wherein the at least onesterol absorption inhibitor is selected from the group consisting ofsterol absorption inhibitors represented by the following Formulae: (a)Formula (III):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (III) above: Ar¹ is R³-substituted aryl; Ar² isR⁴-substituted aryl; Ar³ is R⁵-substituted aryl; Y and Z areindependently selected from the group consisting of —CH₂—, —CH(loweralkyl)- and —C(dilower alkyl)-; A is selected from —O—, —S—, —S(O)— or—S(O)₂—; R is selected from the group consisting of —OR⁶, —O(CO)R⁶,—O(CO)OR⁹ and —O(CO)NR⁶R⁷; R² is selected from the group consisting ofhydrogen, lower alkyl and aryl; or R¹ and R² together are ═O; q is 1, 2or 3; p is 0, 1, 2, 3 or 4; R⁵ is 1-3 substituents independentlyselected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁹, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂-lower alkyl, —NR⁶SO₂-aryl, —CONR⁶R⁷, —COR⁶,—SO₂NR⁶R⁷, S(O)₀₋₂-alkyl, S(O)₀₋₂-aryl, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, o-halogeno, m-halogeno, o-lower alkyl, m-loweralkyl, -(lower alkylene)-COOR⁶, and —CH═CH—COOR⁶; R³ and R⁴ areindependently 1-3 substituents independently selected from the groupconsisting of R⁵, hydrogen, p-lower alkyl, aryl, —NO₂, —CF₃ andp-halogeno; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; and R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; (b)Formula (IV):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (IV) above: A is selected from the group consistingof R²-substituted heterocycloalkyl, R²-substituted heteroaryl,R²-substituted benzofused heterocycloalkyl, and R²-substitutedbenzofused heteroaryl; Ar¹ is aryl or R³-substituted aryl; Ar² is arylor R²-substituted aryl; Q is a bond or, with the 3-position ring carbonof the azetidinone, forms the spiro group

and R¹ is selected from the group consisting of: —(CH₂)_(q)—, wherein qis 2-6, provided that when Q forms a spiro ring, q can also be zero or1; —(CH₂)_(e)-G-(CH₂)_(r)—, wherein G is —O—, —C(O)—, phenylene, —NR⁸—or —S(O)₀₋₂, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆ alkenylene)-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R⁵ is selected from:

R⁶ and R⁷ are independently selected from the group consisting of —CH₂—,—CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R⁵ together with an adjacent R⁶, or R⁵ together with anadjacent R⁷, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and b areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R⁶ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1; provided that when R⁷is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1; provided that when a is 2 or3, the R⁶'s can be the same or different; and provided that when b is 2or 3, the R⁶'s can be the same or different; and when Q is a bond, R¹also can be selected from:

where M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independentlyselected from the group consisting of —CH₂—, —CH(C₁-C₆ alkyl)- and—C(di-(C₁-C₆) alkyl); R¹⁰ and R¹² are independently selected from thegroup consisting of —OR¹⁴, —O(CO)R¹⁴, —O(CO)OR¹⁶ and —O(CO)NR¹⁴R¹⁵; R¹¹and R¹³ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl and aryl; or R¹⁰ and R¹¹ together are ═O, or R¹²and R¹³ together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or1; t is 0 or 1; m, n and p are independently 0-4; provided that at leastone of s and t is 1, and the sum of m, n, p, s and t is 1-6; providedthat when p is 0 and t is 1, the sum of m, s and n is 1-5; and providedthat when p is 0 and s is 1, the sum of m, t and n is 1-5; v is 0 or 1;j and k are independently 1-5, provided that the sum of j, k and v is1-5; R² is 1-3 substituents on the ring carbon atoms selected from thegroup consisting of hydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl, R¹⁷-substitutedaryl, R¹⁷-substituted benzyl, R¹⁷-substituted benzyloxy, R¹⁷-substitutedaryloxy, halogeno, —NR¹⁴R¹⁵, NR¹⁴R¹⁵(C₁-C₆alkylene)-,—NR¹⁴R¹⁵C(O)(C₁-C₆alkylene)-,—NHC(O)R¹⁶, OH, C₁-C₆ alkoxy,—OC(O)R¹⁶, —COR¹⁴, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, NO₂,—S(O)₀₋₂R¹⁶, —SO₂NR¹⁴R¹⁵ and —(C₁-C₆ alkylene)COOR¹⁴; when R² is asubstituent on a heterocycloalkyl ring, R² is as defined, or is ═O or

and, where R² is a substituent on a substitutable ring nitrogen, it ishydrogen, (C₁-C₆)alkyl, aryl, (C₁-C₆)alkoxy, aryloxy,(C₁-C₆)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH₂)₁₋₆CONR¹⁸R¹⁸,

wherein J is —O—, —NH—, —NR¹⁸— or —CH₂—; R³ and R⁴ are independentlyselected from the group consisting of 1-3 substituents independentlyselected from the group consisting of (C₁-C₆)alkyl, —OR¹⁴, —O(CO)R¹⁴,—O(CO)OR¹⁶, —O(CH₂)₁₋₅OR¹⁴, —O(CO)NR¹⁴R¹⁵,—NR¹⁴R¹⁵, —NR¹⁴(CO)R¹⁵,—NR¹⁴(CO)OR¹⁶, —NR¹⁴(CO)NR¹⁵R¹⁹, —NR¹⁴SO₂R¹⁶, —COOR¹⁴, —CONR¹⁴R¹⁵,—COR¹⁴, SO₂NR¹⁴R¹⁵, S(O)₀₋₂R¹⁶, —O(CH₂)₁₋₁₀—COOR¹⁴,—O(CH₂)₁₋₁₀CONR¹⁴R¹⁵, —(C₁-C₆ alkylene)-COOR¹⁴, —CH═CH—COOR¹⁴, —CF₃,—CN, —NO₂ and halogen; R⁸ is hydrogen, (C₁-C₆)alkyl, aryl (C₁-C₆)alkyl,—C(O)R¹⁴ or —COOR¹⁴; R⁹ and R¹⁷ are independently 1-3 groupsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁴R¹⁵, OH and halogeno; R¹⁴and R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R¹⁶ is(C₁-C₆)alkyl, aryl or R¹⁷-substituted aryl; R¹⁸ is hydrogen or(C₁-C₆)alkyl; and R¹⁹ is hydrogen, hydroxy or (C₁-C₆)alkoxy; (c) Formula(V):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (V) above: Ar¹ is aryl, R¹⁰-substituted aryl orheteroaryl; Ar² is aryl or R⁴-substituted aryl; Ar³ is aryl orR⁵-substituted aryl; X and Y are independently selected from the groupconsisting of —CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-; R is—OR⁶, —O(CO)R⁶, —O(CO)OR⁶, or —O(CO)NR⁶R⁷; R¹ is hydrogen, lower alkylor aryl; or R and R¹ together are ═O; q is 0 or 1; r is 0, 1 or 2; m andn are independently 0, 1, 2, 3, 4 or 5; provided that the sum of m, nand q is 1, 2, 3, 4 or 5; R⁴ is 1-5 substituents independently selectedfrom the group consisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹,—O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹,—NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷,S(O)₀₋₂R⁹,—O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁵ is 1-5 substituents independently selected from thegroup consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂, halogen, -(lower alkylene)COOR⁶ and—CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, lower alkyl, aryl and aryl-substituted loweralkyl; R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl; and R¹⁰is 1-5 substituents independently selected from the group consisting oflower alkyl, —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶,—CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, —S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —CF₃, —CN, —NO₂ and halogen; (d) Formula (VI):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein: R₁ is

R₂ and R₃ are independently selected from the group consisting of:—CH₂—, —CH(lower alkyl)-, —C(di-lower alkyl)-, —CH═CH— and —C(loweralkyl)=CH—; or R₁ together with an adjacent R₂, or R₁ together with anadjacent R₃, form a —CH═CH— or a —CH═C(lower alkyl)- group; u and v areindependently 0, 1, 2 or 3, provided both are not zero; provided thatwhen R₂ is —CH═CH— or —C(lower alkyl)═CH—, v is 1; provided that when R₃is —CH—CH— or —C(lower alkyl)═CH—, u is 1; provided that when v is 2 or3, the R₂'s can be the same or different; and provided that when u is 2or 3, the R₃'s can be the same or different; R₄ is selected fromB—(CH₂)_(m)C(O)—, wherein m is 0, 1, 2, 3, 4 or 5; B—(CH₂)_(q)—, whereinq is 0, 1, 2, 3, 4, 5 or 6; B—(CH₂)_(e)-Z-(CH₂)_(r)—, wherein Z is —O—,—C(O)—, phenylene, —N(R₈)— or —S(O)₀₋₂—, e is 0, 1, 2, 3, 4 or 5and r is0, 1, 2, 3, 4 or 5, provided that the sum of e and r is 0, 1, 2, 3, 4, 5or 6; B—(C₂-C₆ alkenylene)-; B—(C₄-C₆ alkadienylene)-;B—(CH₂)_(t)-Z-(C₂-C₆ alkenylene)-, wherein Z is as defined above, andwherein t is 0, 1, 2 or 3, provided that the sum of t and the number ofcarbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;B—(CH₂)_(f)—V—(CH₂)_(g)—, wherein V is C₃-C₆ cycloalkylene, f is 1, 2,3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and gis 1, 2, 3, 4, 5 or 6; B—(CH₂)_(t)—V—(C₂-C₆ alkenylene)- or B—(C₂-C₆alkenylene)-V—(CH₂)_(t)—, wherein V and t are as defined above, providedthat the sum of t and the number of carbon atoms in the alkenylene chainis 2, 3, 4, 5 or 6; B—(CH₂)_(a)-Z-(CH₂)_(b)—V—(CH₂)_(d)—, wherein Z andV are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; orT-(CH₂)_(s)—, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1,2, 3, 4, 5 or 6; or R₁ and R₄ together form the group

B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl,heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selectedfrom the group consisting of pyrrolyl, pyridinyl, pyrimidinyl,pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,oxazolyl and furanyl, and for nitrogen-containing heteroaryls, theN-oxides thereof, or

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl loweralkanedioyl, allyloxy, —CF₃, —OCF₃, benzyl, R₇-benzyl, benzyloxy,R₇-benzyloxy, phenoxy, R₇-phenoxy, dioxolanyl, NO₂,—N(R₈)(R₉),N(R₈)(R₉)-lower alkylene-, N(R₈)(R₉)-lower alkylenyloxy-, OH, halogeno,—CN, —N₃, —NHC(O)OR₁₀, —NHC(O)R₁₀, R₁₁O₂SNH—, (R₁₁O₂S)₂N—, —S(O)₂NH₂,—S(O)₀₋₂R₈,tert-butyldimethyl-silyloxymethyl, —C(O)R₁₂, —COOR₁₉,—CON(R₈)(R₉), —CH═CHC(O)R₁₂, -lower alkylene-C(O)R₁₂, R₁₀C(O)(loweralkylenyloxy)-, N(R₈)(R₉)C(O)(lower alkylenyloxy)- and

for substitution on ring carbon atoms, and the substituents on thesubstituted heteroaryl ring nitrogen atoms, when present, are selectedfrom the group consisting of lower alkyl, lower alkoxy, —C(O)OR₁₀,—C(O)R₁₀, OH, N(R₈)(R₉)-lower alkylene-,N(R₈)(R₉)-lower alkylenyloxy-,—S(O)₂NH₂ and 2-(trimethylsilyl)-ethoxymethyl; R₇ is 1-3 groupsindependently selected from the group consisting of lower alkyl, loweralkoxy, —COOH, NO₂, —N(R₈)(R₉), OH, and halogeno; R₈ and R₉ areindependently selected from H or lower alkyl; R₁₀ is selected from loweralkyl, phenyl, R₇-phenyl, benzyl or R₇-benzyl; R₁₁ is selected from OH,lower alkyl, phenyl, benzyl, R₇-phenyl or R₇-benzyl; R₁₂ is selectedfrom H, OH, alkoxy, phenoxy, benzyloxy,

—N(R₈)(R₉), lower alkyl, phenyl or R₇-phenyl; R₁₃ is selected from —O—,—CH₂—, —NH—, —N(lower alkyl)- or —NC(O)R₁₉; R₁₅, R₁₆ and R₁₇ areindependently selected from the group consisting of H and the groupsdefined for W; or R₁₅ is hydrogen and R₁₆ and R₁₇, together withadjacent carbon atoms to which they are attached, form a dioxolanylring; R₁₉ is H, lower alkyl, phenyl or phenyl lower alkyl; and R₂₀ andR₂₁ are independently selected from the group consisting of phenyl,W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl,indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substitutedheteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryland cyclopropyl, wherein heteroaryl is as defined above; (e) Formula(VIIA) or (VIIB):

or a pharmaceutically acceptable salt or solvate thereof, wherein: A is—CH═CH—, —C≡C— or —(CH₂)_(p)— wherein p is 0, 1 or 2; B is

B′ is

D is —(CH₂)_(m)C(O)— or —(CH₂)_(q)— wherein m is 1, 2, 3 or 4 and q is2, 3 or 4; E is C₁₀ to C₂₀ alkyl or —C(O)—(C₉ to C₁₉)-alkyl, wherein thealkyl is straight or branched, saturated or containing one or moredouble bonds; R is hydrogen, C₁-C₁₅ alkyl, straight or branched,saturated or containing one or more double bonds, or B—(CH₂)_(r)—,wherein r is 0, 1, 2, or 3; R₁, R₂, R₃, R_(1′), R_(2′), and R_(3′) areindependently selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino,dilower alkylamino, —NHC(O)OR₅, R₆O₂SNH— and —S(O)₂NH₂; R₄ is

wherein n is 0, 1, 2 or 3; R₅ is lower alkyl; and R₆ is OH, lower alkyl,phenyl, benzyl or substituted phenyl wherein the substituents are 1-3groups independently selected from the group consisting of lower alkyl,lower alkoxy, carboxy, NO₂, NH₂, OH, halogeno, lower alkylamino anddilower alkylamino; or a pharmaceutically acceptable salt thereof or aprodrug thereof; (f) Formula (VIII):

or a pharmaceutically acceptable salt thereof or a solvate thereof,wherein, in Formula (VIII) above, R²⁶ is H or OG¹; G and G¹ areindependently selected from the group consisting of H,

and

provided that when R²⁶ is H or OH, G is not H; R, R^(a) and R^(b) areindependently selected from the group consisting of H, —OH, halogeno,—NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy or —W—R³⁰; W is independentlyselected from the group consisting of —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl and aryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R^(3a) and R^(4a) areindependently selected from the group consisting of H, (C₁-C₆)alkyl,aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl and —C(O)aryl; R³⁰ is selected fromthe group consisting of R³²-substituted T,R³²-substituted-T-(C₁-C₆)alkyl, R³²-substituted-(C₂-C₄)alkenyl,R³²-substituted-(C₁-C₆)alkyl, R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is selected from thegroup consisting of H and (C₁-C₄)alkyl; T is selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl,imidazolyl and pyridyl; R³² is independently selected from 1-3substituents independently selected from the group consisting ofhalogeno, (C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy,methylenedioxy, oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl, —N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl,—C(O)—N((C₁-C₄)alkyl)₂, —C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy andpyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹, the nitrogen towhich it is attached and R³² form a pyrrolidinyl, piperidinyl,N-methyl-piperazinyl, indolinyl or morpholinyl group, or a(C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl group; Ar¹ is aryl orR¹⁰-substituted aryl; Ar² is aryl or R¹¹-substituted aryl; Q is a bondor, with the 3-position ring carbon of the azetidinone, forms the spirogroup

and R¹ is selected from the group consisting of —(CH₂)_(q)—, wherein qis 2-6, provided that when Q forms a spiro ring, q can also be zero or1; —(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²—or —S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; —(C₂-C₆)alkenylene-; and —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆ cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; R¹² is

R¹³ and R¹⁴ are independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)=CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare independently 0, 1, 2 or 3, provided both are not zero; providedthat when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1; provided thatwhen R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1; provided that when ais 2 or 3, the R¹³'s can be the same or different; and provided thatwhen b is 2 or 3, the R¹⁴'s can be the same or different; and when Q isa bond, R¹ also can be:

M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are independently selectedfrom the group consisting of —CH₂—, —CH(C₁-C₆)alkyl- and—C(di-(C₁-C₆)alkyl); R¹⁰ and R¹¹ are independently selected from thegroup consisting of 1-3 substituents independently selected from thegroup consisting of (C₁-C₆)alkyl, —OR¹⁹, —O(CO)R¹⁹, —O(CO)OR²¹,—O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰, —NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹,—NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹, —CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰,S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹,—O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃, —CN, —NO₂ and halogen; R¹⁵ andR¹⁷ are independently selected from the group consisting of —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹ and —O(CO)NR¹⁹R²⁰; R¹⁶ and R¹⁸ are independentlyselected from the group consisting of H, (C₁-C₆)alkyl and aryl; or R¹⁵and R¹⁶ together are ═O, or R¹⁷ and R¹⁸ together are ═O; d is 1,2 or 3;h is 0, 1, 2, 3 or 4; s is 0 or 1; t is 0 or 1; m, n and p areindependently 0-4; provided that at least one of s and t is 1, and thesum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1,the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1,the sum of m, t and n is 1-5; v is 0 or 1; j and k are independently1-5, provided that the sum of j, k and v is 1-5; and when Q is a bondand R¹ is

Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are independently selected from the group consisting of H,(C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are independently 1-3groups independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halogeno; andR²⁵ is H, —OH or (C₁-C₆)alkoxy; and (g) Formula (IX):

or a pharmaceutically acceptable salt or solvate thereof, wherein inFormula (IX): R¹ is selected from the group consisting of H, G, G¹, G²,—SO₃H and —PO₃H;

G is selected from the group consisting of: H, wherein R, R^(a) andR^(b) are each independently selected from the group consisting of H,—OH, halo, —NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)alkoxy or —W—R³⁰; W isindependently selected from the group consisting of —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R² and R⁶ areeach independently selected from the group consisting of H,(C₁-C₆)alkyl, acetyl, aryl and aryl(C₁-C₆)alkyl; R³, R⁴, R⁵, R⁷, R_(3a)and R^(4a) are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, acetyl, aryl(C₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl and—C(O)aryl; R³⁰ is independently selected from the group consisting ofR³²-substituted T, R³²-substituted-T-(C₁-C₆)alkyl,R³²-substituted-(C₂-C₄)alkenyl, R³²-substituted-(C₁-C₆)alkyl,R³²-substituted-(C₃-C₇)cycloalkyl andR³²-substituted-(C₃-C₇)cycloalkyl(C₁-C₆)alkyl; R³¹ is independentlyselected from the group consisting of H and (C₁-C₄)alkyl; T isindependently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R³² isindependently selected from 1-3 substituents which are eachindependently selected from the group consisting of H, halo,(C₁-C₄)alkyl, —OH, phenoxy, —CF₃, —NO₂, (C₁-C₄)alkoxy, methylenedioxy,oxo, (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,—N(CH₃)₂, —C(O)—NH(C₁-C₄)alkyl, —C(O)—N((C₁-C₄)alkyl)₂,—C(O)—(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkoxy and pyrrolidinylcarbonyl; or R³²is a covalent bond and R³¹, the nitrogen to which it is attached and R³²form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl ormorpholinyl group, or a (C₁-C₄)alkoxycarbonyl-substituted pyrrolidinyl,piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G¹ isrepresented by the structure:

wherein R³³ is independently selected from the group consisting ofunsubstituted alkyl, R³⁴-substituted alkyl, (R³⁵)(R³⁶)alkyl-,

R³⁴ is one to three substituents, each R³⁴ being independently selectedfrom the group consisting of HOOC—, HO—, HS—, (CH₃)S—, H₂N—,(NH₂)(NH)C(NH)—, (NH₂)C(O)— and HOOCCH(NH₃ ⁺)CH₂SS—; R³⁵ isindependently selected from the group consisting of H and NH₂—; R³⁶ isindependently selected from the group consisting of H, unsubstitutedalkyl, R³⁴-substituted alkyl, unsubstituted cycloalkyl andR³⁴-substituted cycloalkyl; G² is represented by the structure:

wherein R³⁷ and R³⁸ are each independently selected from the groupconsisting of (C₁-C₆)alkyl and aryl; R²⁶ is one to five substituents,each R²⁶ being independently selected from the group consisting of: a)H; b) —OH; c) —OCH₃; d) fluorine; e) chlorine; f) —O-G; g) —O-G¹; h)—O-G²; i) —SO₃H; and j) —PO₃H; provided that when R¹ is H, R²⁶ is not H,—OH, —OCH₃ or —O-G; Ar¹ is aryl, R¹⁰-substituted aryl, heteroaryl orR¹⁰-substituted heteroaryl; Ar² is aryl, R¹¹-substituted aryl,heteroaryl or R¹¹-substituted heteroaryl; L is selected from the groupconsisting of: a) a covalent bond; b) —(CH₂)_(q)—, wherein q is 1-6; c)—(CH₂)_(e)-E-(CH₂)_(r)—, wherein E is —O—, —C(O)—, phenylene, —NR²²— or—S(O)₀₋₂—, e is 0-5 and r is 0-5, provided that the sum of e and r is1-6; d) —(C₂-C₆)alkenylene-; e) —(CH₂)_(f)—V—(CH₂)_(g)—, wherein V isC₃-C₆cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of fand g is 1-6; and f)

wherein M is —O—, —S—, —S(O)— or —S(O)₂—; X, Y and Z are eachindependently selected from the group consisting of —CH₂—, —CH(C₁-C₆)alkyl- and —C(di-(C₁-C₆)alkyl )-; R⁸ is selected from the groupconsisting of H and alkyl; R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of (C₁-C₆)alkyl, —OR¹⁹,—O(CO)R¹⁹, —O(CO)OR²¹, —O(CH₂)₁₋₅OR¹⁹, —O(CO)NR¹⁹R²⁰, —NR¹⁹R²⁰,—NR¹⁹(CO)R²⁰, —NR¹⁹(CO)OR²¹, —NR¹⁹(CO)NR²⁰R²⁵, —NR¹⁹SO₂R²¹, —COOR¹⁹,—CONR¹⁹R²⁰, —COR¹⁹, —SO₂NR¹⁹R²⁰, S(O)₀₋₂R²¹, —O(CH₂)₁₋₁₀—COOR¹⁹,—O(CH₂)₁₋₁₀CONR¹⁹R²⁰, —(C₁-C₆ alkylene)-COOR¹⁹, —CH═CH—COOR¹⁹, —CF₃,—CN, —NO₂ and halo; R¹⁵ and R¹⁷ are each independently selected from thegroup consisting of —OR¹⁹, —OC(O)R¹⁹, —OC(O)OR²¹, —OC(O)NR¹⁹R²⁰; R¹⁶ andR¹⁸ are each independently selected from the group consisting of H,(C₁-C₆)alkyl and aryl; or R¹⁵ and R¹⁶ together are ═O, or R¹⁷and R¹⁸together are ═O; d is 1, 2 or 3; h is 0, 1, 2, 3 or 4; s is 0 or 1; t is1 or 1; m, n and p are each independently selected from 0-4; providedthat at least one of s and t is 1, and the sum of m, n, p, s and t is1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5;and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;v is 0 or 1; j and k are each independently 1-5, provided that the sumof j, k and v is 1-5; Q is a bond, —(CH₂)_(q)—, wherein q is 1-6, or,with the 3-position ring carbon of the azetidinone, forms the spirogroup

wherein R¹² is

R¹³ and R¹⁴ are each independently selected from the group consisting of—CH₂—, —CH(C₁-C₆ alkyl)-, —C(di-(C₁-C₆) alkyl), —CH═CH— and —C(C₁-C₆alkyl)═CH—; or R¹² together with an adjacent R¹³, or R¹² together withan adjacent R¹⁴, form a —CH═CH— or a —CH═C(C₁-C₆ alkyl)- group; a and bare each independently 0, 1, 2 or 3, provided both are not zero;provided that when R¹³ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, a is 1;provided that when R¹⁴ is —CH═CH— or —C(C₁-C₆ alkyl)═CH—, b is 1;provided that when a is 2 or 3, the R¹³'s can be the same or different;and provided that when b is 2 or 3, the R¹⁴'s can be the same ordifferent; and when Q is a bond and L is

then Ar¹ can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;R¹⁹ and R²⁰ are each independently selected from the group consisting ofH, (C₁-C₆)alkyl, aryl and aryl-substituted (C₁-C₆)alkyl; R²¹ is(C₁-C₆)alkyl, aryl or R²⁴-substituted aryl; R²² is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, —C(O)R¹⁹ or —COOR¹⁹; R²³ and R²⁴ are each independentlyselected from the group consisting of 1-3 substituents which are eachindependently selected from the group consisting of H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, —COOH, NO₂, —NR¹⁹R²⁰, —OH and halo; and R²⁵ is H, —OH or(C₁-C₆)alkoxy.